Bio

Clinical Focus


  • Critical Care Medicine
  • Lung and Heart-Lung Transplantation
  • Pulmonary Disease

Academic Appointments


Administrative Appointments


  • Member, National Lung Review Board, United Network for Organ Sharing (2008 - 2010)
  • Memeber, Pulmonary Tx Registries and Database Workforce, International Society for Heart and Lung Transplantation (2009 - Present)
  • Member, Interdisciplinary Critical Care Professional Practice Evaluation Committee, Stanford University Medical Center (2009 - Present)

Professional Education


  • Fellowship:Louisiana State University (1999) LA
  • Internship:St Joseph Mercy Medical Clinic (1993) MI
  • Medical Education:Punjab University Christian Medical College (1991) India
  • Board Certification: Pulmonary Disease, American Board of Internal Medicine (1998)
  • Fellowship:Stanford University Medical Center (2005) CA
  • Residency:Detroit Receiving Hospital (1996) MI
  • MPH, Tulane University, Public Health, Epidemiology (2000)
  • Board Certification: Critical Care Medicine, American Board of Internal Medicine (2001)
  • MD, Christian Medical College, Medicine (1991)

Research & Scholarship

Current Research and Scholarly Interests


1. Use of an administrative database (UNOS) to study lung transplant outcomes.
2. Expression of the plasminogen activator inhibitor (PAI) 1 antibody in peripheral blood after lung transplantation and its association with bronchiolitis obliterans syndrome (chronic rejection).
3. Impact of airway hypoxia, due to lack of bronchial circulation, on long-term lung transplant outcomes.
4. CMV specific T-cell immunity in lung transplant recipients and its impact on acute rejection.

Teaching

2013-14 Courses


Publications

Journal Articles


  • Donor-Derived West Nile Virus Infection in Solid Organ Transplant Recipients: Report of Four Additional Cases and Review of Clinical, Diagnostic, and Therapeutic Features. Transplantation Winston, D., Holenarasipur, V., Rabe, I., Dhillon, G., Mulligan, D., Hong, J., Busuttil, R., Nowicki, M., Mone, T., Civen, R., Tecle, S., Trivedi, K., Hocevar, S. 2014
  • West Nile Virus RNA in Tissues from Donor Associated with Transmission to Organ Transplant Recipients EMERGING INFECTIOUS DISEASES Blau, D. M., Rabe, I. B., Bhatnagar, J., Civen, R., Trivedi, K. K., Rollin, D., Hocevar, S. N., Kuehnert, M., Staples, J. E., Zaki, S. R., Fischer, M. 2013; 19 (9): 1518-1520

    Abstract

    We identified West Nile virus (WNV) RNA in skin, fat, muscle, tendon, and bone marrow from a deceased donor associated with WNV transmission through solid organ transplantation. WNV could not be cultured from the RNA-positive tissues. Further studies are needed to determine if WNV can be transmitted from postmortem tissues.

    View details for DOI 10.3201/eid1909.130365

    View details for Web of Science ID 000328173800026

    View details for PubMedID 23965573

  • Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Science translational medicine Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Qian, J., Dhillon, G., Gera, L., Farkas, L., Rabinovitch, M., Zamanian, R. T., Inayathullah, M., Fridlib, M., Rajadas, J., Peters-Golden, M., Voelkel, N. F., Nicolls, M. R. 2013; 5 (200): 200ra117-?

    Abstract

    Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease-associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting.

    View details for DOI 10.1126/scitranslmed.3006674

    View details for PubMedID 23986401

  • New methods for monitoring dynamic airway tissue oxygenation and perfusion in experimental and clinical transplantation AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Khan, M. A., Dhillon, G., Jiang, X., Lin, Y., Nicolls, M. R. 2012; 303 (10): L861-L869

    Abstract

    A dual circulation, supplied by bronchial and pulmonary artery-derived vessels, normally perfuses the airways from the trachea to the terminal bronchioles. This vascular system has been highly conserved through mammalian evolution and is disrupted at the time of lung transplantation. In most transplant centers, this circulation is not restored. The Papworth Hospital Autopsy study has revealed that an additional attrition of periairway vessels is associated with the development of chronic rejection, otherwise known as the bronchiolitis obliterans syndrome (BOS). Experimental studies subsequently demonstrated that airway vessels are subject to alloimmune injury and that the loss of a functional microvascular system identifies allografts that cannot be rescued with immunosuppressive therapy. Therefore, surgical and medical strategies, which preserve the functionality of the existent vasculature in lung transplant patients, may conceivably limit the incidence of BOS. Given these unique anatomic and physiological considerations, there is an emerging rationale to better understand the perfusion and oxygenation status of airways in transplanted lungs. This article describes novel methodologies, some newly developed by our group, for assessing airway tissue oxygenation and perfusion in experimental and clinical transplantation.

    View details for DOI 10.1152/ajplung.00162.2012

    View details for Web of Science ID 000311208400003

    View details for PubMedID 23002078

  • Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients CLINICAL TRANSPLANTATION Dhillon, G. S., Valentine, V. G., Levitt, J., Patel, P., Gupta, M. R., Duncan, S. R., Seoane, L., Weill, D. 2012; 26 (1): 105-110

    Abstract

    Bronchiolitis obliterans syndrome (BOS) is the major limitation to long-term survival following lung transplantation and strategies to reduce its incidence have remained elusive. Macrolides may stabilize lung function in patients with established BOS. Their role, however, in prevention of BOS remains unexamined.Survival and BOS-free survival of 102 lung allograft recipients (LARs), transplanted at a single center between July 1995 and December 2001 who routinely received clarithromycin, were compared with two different control groups. The first control group consisted of 44 LARs from the same center who were transplanted from January 2002 onwards and did not receive clarithromycin. The second control group consisted of a contemporaneous cohort of 5089 recipients, transplanted between 1995 and 2001, reported to the United Network for Organ Sharing database.When compared with the first control group, BOS-free survival was reduced in LARs receiving clarithromycin. Univariate (hazard ratio [HR] 3.13, p-value = 0.004) and multivariate (HR 3.49, p-value = 0.04) analyses showed that routine use of clarithromycin was associated with an increased risk of developing BOS. When compared with the second control group, the five-yr survival of clarithromycin group was similar (p-value = 0.24).Routine use of clarithromycin does not delay development of BOS or improve survival.

    View details for DOI 10.1111/j.1399-0012.2011.01420.x

    View details for Web of Science ID 000300715100025

    View details for PubMedID 21352378

  • CD4(+) T Cells and Complement Independently Mediate Graft Ischemia in the Rejection of Mouse Orthotopic Tracheal Transplants CIRCULATION RESEARCH Khan, M. A., Jiang, X., Dhillon, G., Beilke, J., Holers, V. M., Atkinson, C., Tomlinson, S., Nicolls, M. R. 2011; 109 (11): 1290-U256

    Abstract

    While microvascular injury is associated with chronic rejection, the cause of tissue ischemia during alloimmune injury is not yet elucidated.We investigated the contribution of T lymphocytes and complement to microvascular injury-associated ischemia during acute rejection of mouse tracheal transplants.Using novel techniques to assess microvascular integrity and function, we evaluated how lymphocyte subsets and complement specifically affect microvascular perfusion and tissue oxygenation in MHC-mismatched transplants. To characterize T cell effects on microvessel loss and recovery, we transplanted functional airway grafts in the presence and absence of CD4(+) and CD8(+) T cells. To establish the contribution of complement-mediated injury to the allograft microcirculation, we transplanted C3-deficient and C3-inhibited recipients. We demonstrated that CD4(+) T cells and complement are independently sufficient to cause graft ischemia. CD8(+) T cells were required for airway neovascularization to occur following CD4-mediated rejection. Activation of antibody-dependent complement pathways mediated tissue ischemia even in the absence of cellular rejection. Complement inhibition by CR2-Crry attenuated graft hypoxia, complement/antibody deposition on vascular endothelium and promoted vascular perfusion by enhanced angiogenesis. Finally, there was a clear relationship between the burden of tissue hypoxia (ischemia×time duration) and the development of subsequent airway remodeling.These studies demonstrated that CD4(+) T cells and complement operate independently to cause transplant ischemia during acute rejection and that sustained ischemia is a precursor to chronic rejection.

    View details for DOI 10.1161/CIRCRESAHA.111.250167

    View details for Web of Science ID 000296872200016

    View details for PubMedID 21998328

  • Regulatory T Cells Limit Vascular Endothelial Injury and Prevent Pulmonary Hypertension CIRCULATION RESEARCH Tamosiuniene, R., Tian, W., Dhillon, G., Wang, L., Sung, Y. K., Gera, L., Patterson, A. J., Agrawal, R., Rabinovitch, M., Ambler, K., Long, C. S., Voelkel, N. F., Nicolls, M. R. 2011; 109 (8): 867-U120

    Abstract

    Pulmonary arterial hypertension (PAH) is an incurable disease associated with viral infections and connective tissue diseases. The relationship between inflammation and disease pathogenesis in these disorders remains poorly understood.To determine whether immune dysregulation due to absent T-cell populations directly contributes to the development of PAH.Vascular endothelial growth factor receptor 2 (VEGFR2) blockade induced significant pulmonary endothelial apoptosis in T-cell-deficient rats but not in immune-reconstituted (IR) rats. T cell-lymphopenia in association with VEGFR2 blockade resulted in periarteriolar inflammation with macrophages, and B cells even prior to vascular remodeling and elevated pulmonary pressures. IR prevented early inflammation and attenuated PAH development. IR with either CD8 T cells alone or with CD4-depleted spleen cells was ineffective in preventing PAH, whereas CD4-depleting immunocompetent euthymic animals increased PAH susceptibility. IR with either CD4(+)CD25(hi) or CD4(+)CD25(-) T cell subsets prior to vascular injury attenuated the development of PAH. IR limited perivascular inflammation and endothelial apoptosis in rat lungs in association with increased FoxP3(+), IL-10- and TGF-?-expressing CD4 cells, and upregulation of pulmonary bone morphogenetic protein receptor type 2 (BMPR2)-expressing cells, a receptor that activates endothelial cell survival pathways.PAH may arise when regulatory T-cell (Treg) activity fails to control endothelial injury. These studies suggest that regulatory T cells normally function to limit vascular injury and may protect against the development of PAH.

    View details for DOI 10.1161/CIRCRESAHA.110.236927

    View details for Web of Science ID 000295368300008

    View details for PubMedID 21868697

  • Lung function, radiological changes and exposure: analysis of ATSDR data from Libby, MT, USA EUROPEAN RESPIRATORY JOURNAL Weill, D., Dhillon, G., Freyder, L., Lefante, J., Glindmeyer, H. 2011; 38 (2): 376-383

    Abstract

    In 2000, the Agency for Toxic Substances and Disease Registry (ATSDR; Atlanta, GA, USA) investigated lung disease in those exposed to the tremolite-contaminated vermiculite mine in Libby, MT, USA. Previously unreported spirometric results are presented here in relation to exposure and radiographic findings. 4,524 study participants were assigned to one of seven mutually exclusive exposure categories. Associations among radiographic findings, spirometric results and exposure were investigated, along with the effect of a reduction in exposure potential when production was moved to a wet process mill in the mid 1970s. Spirometry data for the total population by smoking status and age were within the normal range. Prevalence of pleural plaque increased with age, but was lowest in the environmentally exposed group (0.42-12.74%) and greatest in the W.R. Grace & Co. mineworkers (20-45.68%). For males, there was a significant (4.5%) effect of pleural plaques on forced vital capacity. For W.R. Grace & Co. workers and household contacts, a reduction in plaque (0.11 versus 1.64%) and in diffuse pleural thickening or costophrenic angle obliteration (1.94 and 0.13%) was noted for those exposed after 1976. These analyses do not support a clinically important reduction in spirometry of this cohort. The 1976 reductions in exposure have led to decrease in radiographic changes.

    View details for DOI 10.1183/09031936.00050210

    View details for Web of Science ID 000293280400021

    View details for PubMedID 21177846

  • Review of Heart-Lung Transplantation at Stanford ANNALS OF THORACIC SURGERY Deuse, T., Sista, R., Weill, D., Tyan, D., Haddad, F., Dhillon, G., Robbins, R. C., Reitz, B. A. 2010; 90 (1): 329-337

    Abstract

    Long-term survival after heart-lung transplantation was first achieved in 1981 at Stanford and a total of 217 heart-lung transplantations had been performed by June 2008. This review summarizes Stanford's cumulative experience with heart-lung transplantation, demonstrates the progress that has been made, and discusses past and persistent problems. Diagnostic tools and treatment options for infectious diseases and rejection have changed and patient survival markedly improved over the almost three decades. Eight patients lived longer than 20 years. Further options to treat infections and strategies to control bronchiolitis obliterans syndrome, the main causes of early and long-term mortality, respectively, are required to achieve routine long-term survival.

    View details for DOI 10.1016/j.athoracsur.2010.01.023

    View details for Web of Science ID 000278998400070

    View details for PubMedID 20609821

  • Lung Transplant Airway Hypoxia A Diathesis to Fibrosis? AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Dhillon, G. S., Zamora, M. R., Roos, J. E., Sheahan, D., Sista, R. R., van der Starre, P., Weill, D., Nicolls, M. R. 2010; 182 (2): 230-236

    Abstract

    Chronic rejection, manifested pathologically as airway fibrosis, is the major problem limiting long-term survival in lung transplant recipients. Airway hypoxia and ischemia, resulting from a failure to restore the bronchial artery (BA) circulation at the time of transplantation, may predispose patients to chronic rejection. To address this possibility, clinical information is needed describing the status of lung perfusion and airway oxygenation after transplantation.To determine the relative pulmonary arterial blood flow, airway tissue oxygenation and BA anatomy in the transplanted lung was compared with the contralateral native lung in lung allograft recipients.Routine perfusion scans were evaluated at 3 and 12 months after transplantation in 15 single transplant recipients. Next, airway tissue oximetry was performed in 12 patients during surveillance bronchoscopies in the first year after transplant and in 4 control subjects. Finally, computed tomography (CT)-angiography studies on 11 recipients were reconstructed to evaluate the post-transplant anatomy of the BAs.By 3 months after transplantation, deoxygenated pulmonary arterial blood is shunted away from the native lung to the transplanted lung. In the first year, healthy lung transplant recipients exhibit significant airway hypoxia distal to the graft anastomosis. CT-angiography studies demonstrate that BAs are abbreviated, generally stopping at or before the anastomosis, in transplant airways.Despite pulmonary artery blood being shunted to transplanted lungs after transplantation, grafts are hypoxic compared with both native (diseased) and control airways. Airway hypoxia may be due to the lack of radiologically demonstrable BAs after lung transplantation.

    View details for DOI 10.1164/rccm.200910-1573OC

    View details for Web of Science ID 000280206700014

    View details for PubMedID 20339145

  • Increasing Lung Allocation Scores Predict Worsened Survival Among Lung Transplant Recipients AMERICAN JOURNAL OF TRANSPLANTATION Liu, V., Zamora, M. R., Dhillon, G. S., Weill, D. 2010; 10 (4): 915-920

    Abstract

    Implemented in 2005, the lung allocation score (LAS) aims to distribute donor organs based on overall survival benefits for all potential recipients, rather than on waiting list time accrued. While prior work has shown that patients with scores greater than 46 are at increased risk of death, it is not known whether that risk is equivalent among such patients when stratified by LAS score and diagnosis. We retrospectively evaluated 5331 adult lung transplant recipients from May 2005 to February 2009 to determine the association of LAS (groups based on scores of < or =46, 47-59, 60-79 and > or =80) and posttransplant survival. When compared with patients with LAS < or = 46, only those with LAS > or = 60 had an increased risk of death (LAS 60-79: hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.21-1.90; LAS > or = 80: HR, 2.03; CI, 1.61-2.55; p < 0.001) despite shorter median waiting list times. This risk persisted after adjusting for age, diagnosis, transplant center volume and donor characteristics. By specific diagnosis, an increased hazard was observed in patients with COPD with LAS > or = 80, as well as those with IPF with LAS > or = 60.

    View details for DOI 10.1111/j.1600-6143.2009.03003.x

    View details for Web of Science ID 000275768300030

    View details for PubMedID 20121747

  • A multi-drug regimen for respiratory syncytial virus and parainfluenza virus infections in adult lung and heart-lung transplant recipients TRANSPLANT INFECTIOUS DISEASE Liu, V., Dhillon, G. S., Weill, D. 2010; 12 (1): 38-44

    Abstract

    Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) can cause significant morbidity and mortality in lung and heart-lung transplant recipients. We evaluated the utility of a multi-drug protocol for the treatment of RSV- and PIV-related infections.RSV or PIV was identified in 25 patients with a total of 29 infectious episodes between January 2006 and December 2007. The study included 20 women and 5 men, mean age 42 +/- 13 years. Fifteen patients had received bilateral lung transplant and the remainder either received single lung or heart-lung transplant. Mean time from transplant to infection was 1192 days. RSV was identified in 23 cases, PIV in 7 cases. Patients underwent treatment with inhaled ribavirin, methylprednisolone, and intravenous immunoglobulin (IVIG). RSV-positive patients were also treated with palivizumab. We retrospectively evaluated their clinical status and pulmonary function for a 1-year interval before and after the date of infection.Average baseline forced expiratory volume in 1 s (FEV(1)) before infection was 2.14 +/- 0.68 L/min. Average decline in FEV(1) was 5.7% at the time of infection. Average FEV(1) during post-treatment follow-up was not significantly different than baseline (2.16 +/- 0.80 L/min). Among patients with bronchiolitis obliterans syndrome (BOS) stages 1, 2, or 3 at the time of infection, average FEV(1) declined by 14.8% and remained lower at 9.1% during follow-up when compared with patients with BOS stages 0 or 0p. No complications resulted from treatment. One patient died during follow-up as a result of pre-existing liver failure.This study of lung and heart-lung transplant recipients infected with RSV and PIV shows that a multi-drug regimen including inhaled ribavirin, corticosteroids, and IVIG (with or without palivizumab) is safe and effective. Prompt diagnosis and therapy for patients with RSV or PIV infections are critical for maintaining lung function.

    View details for DOI 10.1111/j.1399-3062.2009.00453.x

    View details for Web of Science ID 000273823500006

    View details for PubMedID 19761558

  • Clinical spectrum of gram-positive infections in lung transplantation TRANSPLANT INFECTIOUS DISEASE Gupta, M. R., Valentine, V. G., Walker, J. E., Lombard, G. A., LaPlace, S. G., Seoane, L., Taylor, D. E., Dhillon, G. S. 2009; 11 (5): 424-431

    Abstract

    Gram-positive (GP) organisms are among the most common cause of infections in early postsurgical and immunocompromised populations. Patients recovering from lung transplantation (LT) are particularly susceptible owing to the physiologic stress imposed by surgery and induction with intense immunosuppression. Sites, types, and timing of GP infections following LT are not well documented. This report describes the clinical spectrum of GP infections and their effects on surgical airway complications (SAC) and bronchiolitis obliterans syndrome (BOS) following LT.Data were collected from 202 patients undergoing 208 LT procedures at a single institution between November 1990 and November 2005. Data were retrospectively analyzed according to timing, location, and causative pathogen.In the median follow-up period of 2.7 years (range, 0-13.6 years), 137 GP infections were confirmed in 72 patients. Sites of infection included respiratory tract (42%), blood (27%), skin, wound and catheter (21%), and other (10%). GP pathogens identified were Staphylococcus species (77%), Enterococcus species (12%), Streptococcus species (6%), Pneumococcus (4%), and Eubacterium lentum (1%). The likelihood of SAC and BOS was increased in lung allograft recipients with GP pneumonia as compared with those without (hazard ratio 2.1; 95% confidence interval=1.5-3.1).GP organisms were responsible for infections in 40% of lung allograft recipients and most commonly isolated from the respiratory tract and blood stream. Staphylococcal species were most frequently identified, 42% of which were methicillin-resistant Staphylococcus aureus (MRSA). Given the strong association of respiratory tract infections with the development of SAC and BOS, empiric antimicrobial strategies after LT should include agents directed against GP organisms, especially MRSA.

    View details for DOI 10.1111/j.1399-3062.2009.00422.x

    View details for Web of Science ID 000270429700006

    View details for PubMedID 19659672

  • Impact of Hepatitis B Core Antibody Positive Donors in Lung and Heart-Lung Transplantation: An Analysis of the United Network for Organ Sharing Database TRANSPLANTATION Dhillon, G. S., Levitt, J., Mallidi, H., Valentine, V. G., Gupta, M. R., Sista, R., Weill, D. 2009; 88 (6): 842-846

    Abstract

    The availability of suitable lung and heart-lung allografts for transplantation remains poor. Accepting organs from donors with positive serological studies for hepatitis B could potentially expand the donor pool. The aim of this study was to assess the impact of donor hepatitis B core antibody (HBcAb) status on outcomes of lung and heart-lung transplant recipients.Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, we compared outcomes of 13,233 recipients of HBcAb negative organs with 333 recipients of HBcAb positive donor organs.We found that the unadjusted 1-year survival of recipients of HBcAb positive donor was worse, but there was no difference in survival after adjusting for baseline donor and recipient differences. On multivariate analysis, recipient and donor age, procedure type, era of transplant, baseline medical condition, diagnosis, and donor hepatitis C antibody status impacted 1- and 5-year survival. However, donor HBcAb status did not impact 1- or 5-year survival posttransplant.Lung and heart-lung allografts from HBcAb positive donors may be safely used, which would increase the number of transplants performed without compromising recipient outcomes.

    View details for DOI 10.1097/TP.0b013e3181b4e1fd

    View details for Web of Science ID 000270270500016

    View details for PubMedID 19920785

  • Effect of Etiology and Timing of Respiratory Tract Infections on Development of Bronchiolitis Obliterans Syndrome JOURNAL OF HEART AND LUNG TRANSPLANTATION Valentine, V. G., Gupta, M. R., Walker, J. E., Seoane, L., Bonvillain, R. W., Lombard, G. A., Weill, D., Dhillon, G. S. 2009; 28 (2): 163-169

    Abstract

    Among the many potential risk factors influencing the development of bronchiolitis obliterans syndrome (BOS), acute cellular rejection is the most frequently identified. Despite the unique susceptibility of the lung allograft to pathogens, the association with respiratory tract infections remains unclear. In this study we analyze the role respiratory tract infections have on the development of BOS after lung transplantation.Data from a single center were analyzed from 161 lung recipients transplanted from November 1990 to November 2005, and who survived >180 days. Univariate and multivariate Cox regression analyses were performed using BOS development and the time-scale was reported with hazard ratios (HRs) and confidence intervals (CIs).Significant findings by univariate analysis per 100 patient-days prior to BOS onset included acute rejection, cytomegalovirus (CMV) pneumonitis, Gram-negative respiratory tract infections, Gram-positive respiratory tract infections and fungal pneumonias. Multivariate analysis indicated acute rejection, Gram-negative, Gram-positive and fungal pneumonias with HRs (CI) of 84 (23 to 309), 6.6 (1.2 to 37), 6,371 (84 to 485,000) and 314 (53 to 1,856) to be associated with BOS, respectively. Acute rejection, CMV pneumonitis, Gram-positive pneumonia and fungal pneumonitis in the first 100 days had HRs (CI) of 1.8 (1.1 to 3.2), 3.1 (1.3 to 6.9), 3.8 (1.5 to 9.4) and 2.1 (1.1 to 4.0), respectively, and acute rejection and fungal pneumonitis in the late post-operative period with HRs (CI) of 2.3 (1.2 to 4.4) and 1.5 (1.1 to 1.9), respectively.In addition to acute rejection, pneumonias with GP, GN and fungal pathogens occurring prior to BOS are independent determinants of chronic allograft dysfunction. Early recognition and treatment of these pathogens in lung transplant recipients may improve long-term outcomes after transplantation.

    View details for DOI 10.1016/j.healun.2008.11.907

    View details for Web of Science ID 000263539900008

    View details for PubMedID 19201342

  • Single-institution Study Evaluating the Utility of Surveillance Bronchoscopy After Lung Transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Valentine, V. G., Gupta, M. R., Weill, D., Lombard, G. A., LaPlace, S. G., Seoane, L., Taylor, D. E., Dhillon, G. S. 2009; 28 (1): 14-20

    Abstract

    Many lung transplant physicians advocate surveillance bronchoscopy with transbronchial lung biopsy and bronchoalveolar lavage (TBB/BAL) to monitor lung recipients despite limited evidence this strategy improves outcomes. This report compares rates of infection (INF), acute rejection (AR), bronchiolitis obliterans syndrome (BOS) and survival in lung allograft recipients managed with surveillance TBB/BAL (SB) versus those with clinically indicated TBB/BAL (CIB).We reviewed 47 consecutive recipients transplanted between March 2002 and August 2005. Of these recipients, 24 consented to a multi-center trial requiring SB and 23 were managed by our usual practice of CIB. Rates of freedom from INF, AR, BOS and survival were compared. BOS and AR were diagnosed according to published guidelines from the International Society for Heart and Lung Transplantation.A total of 240 TBB/BALs were performed. CIB and SB groups underwent 84 (3.7 +/- 3.4/patient) and 156 (6.5 +/- 2.0/patient) TBB/BALs, respectively. In the SB group, 54 (2.2 +/- 1.6/patient) TBB/BALs were true surveillance procedures, whereas 102 (4.2 +/- 2.3/patient) were clinically indicated. No AR episode requiring treatment was detected by true surveillance. Freedom from respiratory INF, AR, BOS and survival in the SB and CIB groups showed no significant differences. Five patients in the CIB group remained stable without requiring TBB/BAL. In the SB group, 4 previously asymptomatic patients developed pneumonia within 2 weeks of surveillance TBB/BAL.With no obvious advantage identified, surveillance bronchoscopy may pose a risk to stable lung transplant recipients. A multi-center, controlled trial is required to validate the utility and safety of surveillance bronchoscopy in lung transplantation.

    View details for DOI 10.1016/j.healun.2008.10.010

    View details for Web of Science ID 000262554400003

    View details for PubMedID 19134525

  • Clostridium difficile colitis in lung transplantation TRANSPLANT INFECTIOUS DISEASE Gunderson, C. C., Gupta, M. R., LOPEZ, F., Lombard, G. A., LaPlace, S. G., Taylor, D. E., Dhillon, G. S., Valentine, V. G. 2008; 10 (4): 245-251

    Abstract

    Clostridium difficile colitis (CDC) is the most common nosocomial infection of the gastrointestinal tract in patients with recent antibiotic use or hospitalization. Lung transplant recipients receive aggressive antimicrobial therapy postoperatively for treatment and prophylaxis of respiratory infections. This report describes the epidemiology of CDC in lung recipients from a single center and explores possible associations with bronchiolitis obliterans syndrome (BOS), a surrogate marker of chronic rejection.Patients were divided into those with confirmed disease (CDC+) and those without disease (CDC-) based on positive C. difficile toxin assay. Because of a bimodal distribution in the time to develop CDC, the early postoperative CDC+ group was analyzed separately from the late postoperative CDC+ cohort with respect to BOS development.Between 1990 and 2005, 202 consecutive patients underwent 208 lung transplantation procedures. Of these, 15 lung recipients developed 23 episodes of CDC with a median follow-up period of 2.7 years (range, 0-13.6). All patients with confirmed disease had at least 1 of the following 3 risk factors: recent antibiotic use, recent hospitalization, or augmentation of steroid dosage. Of the early CDC+ patients, 100% developed BOS, but only 52% of the late CDC+ patients developed BOS, either preceding or following infection.CDC developed in 7.4% of lung transplant patients with identified risk factors, yielding a cumulative incidence of 14.7%. The statistical association of BOS development in early CDC+ patients suggests a relationship between early infections and future chronic lung rejection.

    View details for DOI 10.1111/j.1399-3062.2008.00305.x

    View details for Web of Science ID 000258399900005

    View details for PubMedID 18312477

  • Ganciclovir for cytomegalovirus: a call for indefinite prophylaxis in lung transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Valentine, V. G., Weill, D., Gupta, M. R., Raper, B., LaPlace, S. G., Lombard, G. A., Bonvillain, R. W., Taylor, D. E., Dhillon, G. S. 2008; 27 (8): 875-881

    Abstract

    Universal ganciclovir (GCV) prophylaxis is a strategy aimed at reducing cytomegalovirus (CMV) infection and delaying the development of bronchiolitis obliterans syndrome (BOS). However, the optimal duration of GCV prophylaxis remains unclear. We report our experience with GCV prophylaxis administered indefinitely and its effect on CMV pneumonitis, BOS and survival after lung transplantation (LT).One hundred fifty-one patients surviving >100 days after LT were analyzed. GCV was given to 130 CMV donor- or recipient-seropositive patients. Data from 90 patients who received indefinite GCV prophylaxis (IND) and 40 patients who discontinued their GCV prophylaxis (STOP) were compared.CMV pneumonitis occurred in 16%, 8%, 17% and 19% of patients in the D+R+, D-R+, D+R- and D-R- groups, respectively. In the STOP cohort, 15 of 40 patients developed CMV pneumonitis (median time 79 days) after GCV was stopped. Ten of these 15 patients developed BOS (median time 116 days) after discontinuing GCV. The risk of CMV pneumonitis in the STOP cohort was significantly higher when GCV prophylaxis was discontinued within the first year. Cumulative incidence of CMV pneumonitis in the IND and STOP groups at 5 years was 2% and 57%, respectively (p < 0.001). BOS-free survival and survival were similar across both groups.Indefinite GCV prophylaxis prevents CMV pneumonitis in 98% of LT recipients. Thirty-eight percent of patients discontinuing prophylaxis developed CMV pneumonitis, 50% of whom progressed to BOS within 1 year. Continuing ganciclovir prophylaxis indefinitely after lung transplantation should be considered.

    View details for DOI 10.1016/j.healun.2008.05.009

    View details for Web of Science ID 000258241200010

    View details for PubMedID 18656801

  • Infections in lung allograft recipients: Ganciclovir era JOURNAL OF HEART AND LUNG TRANSPLANTATION Valentine, V. G., Bonvillain, R. W., Gupta, M. R., Lombard, G. A., LaPlace, S. G., Dhillon, G. S., Wang, G. 2008; 27 (5): 528-535

    Abstract

    Infections are common after lung transplantation. This report analyzes infections and associated pathogens identified in 202 lung transplant recipients.Infections were tallied according to sites of infection and associated pathogen(s). Infection events were also categorized by post-operative Days 0 to 100, 101 to 365, and after 365, and normalized to 100 patient-days before and after bronchiolitis obliterans syndrome (BOS).From November 1990 to November 2005, 202 patients received 208 lung transplants. The follow-up was 702.4 patient-years. A total of 178 lung transplant patients developed 859 infections, with 944 pathogens identified. Infections were in the lung in 559 (65.1%), mucocutaneous (skin, wound, catheter-related, and oral) in 88 (10.2%), in the blood in 85 (9.8%), and in other sites (urine, bowel, eye, and peritoneum) in 127 (14.8%). Most lung pathogens were bacterial (83.6%), and 57.9% were Pseudomonas aeruginosa. Fungi comprised 10.6%, with Aspergillus spp the most common (67.1%) isolate. Cytomegalovirus pneumonitis was seen in 4.3% of respiratory infections. BOS was diagnosed in 87 patients (43.1% of the total). Of all infections seen in the BOS population, there were 0.42 episodes/100 patient-days and 0.70 episodes/100 patient-days before and after BOS, respectively (p = 0.5).These data provide an updated infection profile in the ganciclovir era after lung transplantation. When compared with pre-ganciclovir times, post-transplant cytomegalovirus infection incidence has notably declined, with filamentous fungi emerging as prevalent pathogens in its place. Such findings are important for refining management of infections in order to offer more stringent treatment against aggressive pathogens.

    View details for DOI 10.1016/j.healun.2007.12.013

    View details for Web of Science ID 000255556900010

    View details for PubMedID 18442719

  • Post-operative infections in cystic fibrosis and non-cystic fibrosis patients after lung transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Bonvillain, R. W., Valentine, V. G., Lombard, G., LaPlace, S., Dhillon, G., Wang, G. 2007; 26 (9): 890-897

    Abstract

    Cystic fibrosis (CF) lung disease is the major cause of mortality in CF patients. Lung transplantation remains a valid therapeutic option. It is unknown whether CF patients receiving healthy lungs have an equal susceptibility to infections when compared with non-CF lung transplant patients. Herein we present the largest analyses to date of the post-operative infection profiles of 60 CF and 60 non-CF lung transplant patients.Bilateral allogeneic lung transplantations and post-transplant management were performed according to standard clinical procedures. Post-operative infections were diagnosed by conventional methods based on clinical symptoms and laboratory cultures.Sixty CF lung-transplant patients developed 278 post-operative respiratory infections, from which 307 pathogens were isolated. Pseudomonas aeruginosa predominantly occupied 60.3%, followed by Mycobacteria spp (7.2%), Aspergillus spp (5.9%) and Staphylococcus spp (5.5%). However, 60 non-CF transplant patients had 154 respiratory infections with 165 pathogens isolated. Pseudomonas aeruginosa was noted in 38.2%, followed by Aspergillus spp (9.7%), Staphylococcus spp (9.7%) and Mycobacteria spp (9.1%). The CF group demonstrated a significantly higher frequency of Pseudomonas respiratory infections than the non-CF group. Interestingly, no significant differences were detected in any infections from other systems including blood, sinuses, skin, wounds, oral cavity, bowel, eyes, peritoneal cavity and urinary tract. Moreover, the CF lung transplant patients had significantly less time free from Pseudomonas infections.The normal lungs implanted into CF patients had significantly higher susceptibility to Pseudomonas infections than those into non-CF patients, suggesting that defective innate immunity outside the lungs contributes to CF lung pathogenesis.

    View details for DOI 10.1016/j.healun.2007.07.002

    View details for Web of Science ID 000249751400004

    View details for PubMedID 17845927

  • The New UNOS Lung Transplantation Allocation System Advances in Pulmonary Hypertension Dhillon G, Doyle R 2005; 4 (2): 12-13
  • Effect of airway pressure display on interobserver agreement in the assessment of vascular pressures in patients with acute lung injury and acute respiratory distress syndrome CRITICAL CARE MEDICINE Rizvi, K., deBoisblanc, B. P., Truwit, J. D., Dhillon, G., Arroliga, A., Fuchs, B. D., Guntupalli, K. K., Hite, D., Hayden, D. 2005; 33 (1): 98-103

    Abstract

    Previous investigations have identified significant interobserver variability in the measurements of central venous pressure and pulmonary artery occlusion pressure in critically ill patients. Large interobserver variability in the measurement of vascular pressures could potentially lead to inappropriate treatment decisions.We postulated that adding an airway pressure signal (Paw) to pressure tracings of central venous pressure and pulmonary artery occlusion pressure would improve interobserver agreement by facilitating identification of end-expiration.To test this hypothesis, six independent experts used a standard protocol to interpret strip-chart recordings of central venous pressure and pulmonary artery occlusion pressure with or without Paw. Two observers were said to agree if their measurements were within 2 mm Hg of each other. SETTING/SUBJECTS/INTERVENTIONS: A total of 459 strip-chart recordings (303 without Paw and 156 with Paw) were obtained from 121 patients enrolled in the ARDSnet Fluids and Catheters Treatment Trial (FACTT) in 16 different hospitals.Agreement within 2 mm Hg between two measurements was 79% for central venous pressure strips without Paw vs. 86% with Paw. For pulmonary artery occlusion pressure, agreement increased from 71% without Paw to 83% with Paw. The increase in agreement with the addition of Paw was greater for strips demonstrating >8 mm Hg phasic respiratory variation compared with strips demonstrating less phasic respiratory variation.Paw display is a simple, inexpensive method to facilitate the identification of end-expiration that can significantly improve interobserver agreement.

    View details for DOI 10.1097/01.CCM.0000150350.70142.E9

    View details for Web of Science ID 000226336300013

    View details for PubMedID 15644654

  • Estimation of pulmonary artery occlusion pressure by an artificial neural network CRITICAL CARE MEDICINE deBoisblanc, B. P., Pellett, A., Johnson, R., Champagne, M., McClarty, E., Dhillon, G., Levitzky, M. 2003; 31 (1): 261-266

    Abstract

    We hypothesized that an artificial neural network, interconnected computer elements capable of adaptation and learning, could accurately estimate pulmonary artery occlusion pressure from the pulsatile pulmonary artery waveform.University medical center.Nineteen closed-chest dogs.Pulmonary artery waveforms were digitally sampled before conventional measurements of pulmonary artery occlusion pressure under control conditions, during infusions of serotonin or histamine, or during volume loading. Individual beats were parsed or separated out. Pulmonary artery pressure, its first time derivative, and the beat duration were used as neural inputs. The neural network was trained by using 80% of all samples and tested on the remaining 20%. For comparison, the regression between pulmonary artery diastolic pressure and pulmonary artery occlusion pressure was developed and tested using the same data sets. As a final test of generalizability, the neural network was trained on data obtained from 18 dogs and tested on data from the remaining dog in a round-robin fashion.The correlation coefficient between the pulmonary artery diastolic pressure estimate of pulmonary artery occlusion pressure and measured pulmonary artery occlusion pressure was.75, whereas that for the neural network estimate of pulmonary artery occlusion pressure was.97 (p <.01 for difference between pulmonary artery diastolic pressure and pulmonary artery occlusion pressure estimates). The pulmonary artery diastolic pressure estimate of pulmonary artery occlusion pressure showed a bias of 0.097 mm Hg (limits of agreement -7.57 to 7.767 mm Hg), whereas the neural network estimate of pulmonary artery occlusion pressure showed a bias of -0.002 mm Hg (-2.592 to 2.588 mm Hg). There was no significant change in the bias of the neural network estimate over the range of values tested. In contrast, the bias for the pulmonary artery diastolic pressure estimate significantly increased with the increasing magnitude of the pulmonary artery occlusion pressure. During round-robin testing, the neural network estimate of pulmonary artery occlusion pressure showed suboptimal performance (correlation coefficient between estimated and measured pulmonary artery occlusion pressure.59).A neural network can accurately estimate pulmonary artery occlusion pressure over a wide range of pulmonary artery occlusion pressure under conditions that alter pulmonary hemodynamics. We speculate that artificial neural networks could provide accurate, real-time estimates of pulmonary artery occlusion pressure in critically ill patients.

    View details for DOI 10.1097/01.CCM.0000045022.14444.DB

    View details for Web of Science ID 000180714800041

    View details for PubMedID 12545026

  • Success of lung transplantation without surveillance bronchoscopy JOURNAL OF HEART AND LUNG TRANSPLANTATION Valentine, V. G., Taylor, D. E., Dhillon, G. S., Knower, M. T., McFadden, P. M., Fuchs, D. M., Kantrow, S. P. 2002; 21 (3): 319-326

    Abstract

    No current evidence demonstrates improved survival or decreased rate of bronchiolitis obliterans syndrome (BOS) despite regularly scheduled fiberoptic bronchoscopy (FOB) with transbronchial biopsy and bronchoalveolar lavage (TBB/BAL) after lung transplantation. Reduced lung function detected with spirometry or oximetry in symptomatic and asymptomatic lung allograft recipients (LARs) may be a more appropriate indication for bronchoscopic sampling.Clinically indicated TBB/BAL without routine invasive surveillance sampling of the transplanted lung does not decrease survival or increase the rate of BOS in LARs.We reviewed 91 consecutive LARs transplanted at Ochsner Clinic between January 1995 and December 1999. Clinical indications for FOB with TBB/BAL include 10% decline in forced expiratory volume in 1 second below baseline; 20% decrease in forced expiratory flow rate between 25% and 75% of the forced vital capacity; or unexplained respiratory symptoms, signs, or fever. Along with demographic and clinical data, 1-year and 3-year survival rates for these 91 LARs were compared with 5,430 LARs from the International Society for Heart and Lung Transplantation (ISHLT) Registry transplanted during the same 60-month period. Ten of the 91 patients did not survive to hospital discharge after transplantation. We divided the remaining 81 LARs into 2 subsets: Group A patients (n = 43) underwent zero to 1 TBB/BAL and Group B patients (n = 38) required more than 1 procedure. Demographic data, rejection, infection, and incidence of BOS were compared between groups.The 1-year and 3-year survival rates in the Ochsner LAR cohort were 85% and 73%, respectively, vs 72% and 57% in the ISHLT cohort p < 0.01. The relative risks of death in the Ochsner group at 1- and 3-years were 0.56 (0.35-0.91) and 0.66 (0.48-0.92), respectively, p < 0.05. The median (range) follow-up was 910 days (60-1,886) for Group A and 961 days (105-1,883) for Group B, p = not significant. We observed twice as many patients with cystic fibrosis and twice as many pneumonia episodes in Group B. The rate of acute rejection in each group was not statistically different. The cumulative incidence of BOS was increased in Group B at 1 year and at 3 years (5% and 56%) when compared with Group A (3% and 13%), p < 0.01.Based on the findings from this observational, single-institution study, clinically indicated TBB/BAL without routine surveillance sampling of the lung allograft is unlikely to pose greater risk than does regularly scheduled bronchoscopy after lung transplantation.

    View details for Web of Science ID 000174396600003

    View details for PubMedID 11897519

  • Inhibition of hematopoietic progenitor cell proliferation by ethanol in human immunodeficiency virus type 1 Tat-expressing transgenic mice ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Prakash, O., Rodriguez, V. E., Tang, Z. Y., Zhou, P., Coleman, R., Dhillon, G., Shellito, J. E., Nelson, S. 2001; 25 (3): 450-456

    Abstract

    A number of hematological abnormalities are associated with both human immunodeficiency virus type 1 (HIV-1) infection and alcohol abuse. There is little information on how alcohol abuse might further influence the survival and growth of hematopoietic progenitors in HIV-infected individuals in the presence of immune system abnormalities and anti-HIV drugs. Because there is evidence that viral transactivator Tat itself can induce hematopoietic suppression, in this study we examined the role of ethanol as a cofactor in transgenic mice that expressed HIV-1 Tat protein.Tat transgenic mice and nontransgenic littermates were given ethanol (20% v/v) and the anti-HIV drug 3'-azido-3'-deoxythymidine (AZT; 1 mg/ml) in drinking water. Immunosuppression in mice was induced by weekly intraperitoneal injections of anti-CD4 antibody. Hematopoiesis was examined by erythroid colony forming unit (CFU-E) and granulocyte/macrophage colony-forming unit (CFU-GM) assays of the bone marrow progenitor cells.Administration of ethanol for 7 weeks resulted in a 50% decrease in the proliferative capacity of CFU-E- and CFU-GM-derived progenitors from transgenic mice compared with that of ethanol-treated nontransgenic controls. Similar decreases also were observed in transgenic mice treated with AZT or a combination of AZT and ethanol. Furthermore, ethanol and AZT were significantly more toxic to the granulopoietic progenitors (40-50% inhibition) than to the erythropoietic progenitors (10-20% inhibition) in Tat transgenic mice. Although a 10 day exposure of Tat transgenic and nontransgenic mice to a combination of ethanol and AZT had no suppressive effect on the erythropoietic and granulopoietic progenitor cells, there was a marked decrease (40-60%) in CFU-GM in mice made immunodeficient by CD4+ T-lymphocyte depletion. The ethanol-treated Tat transgenic mice but not the nontransgenic litter-mates also showed a significant decrease (25%) in CFU-GM.Our in vivo study strongly suggests that ethanol ingestion in HIV-1-infected individuals, particularly those on antiretroviral drugs, might increase bone marrow toxicity and contribute to HIV-1-associated hematopoietic impairment.

    View details for Web of Science ID 000167594300018

    View details for PubMedID 11290858

Books and Book Chapters


  • Critical Care and Hematopoietic Stem Cell Recipients Thomas’ Hematopoietic Cell Transplantation 4th ed. Dhillon, G., Rizk, N. 2009: 1539-50
  • Lung Under Stress Pulmonary Pathophysiology Dhillon, G., Kantrow, S. McGraw Hill. 1999: 313-331

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