David C. Neujahr

Efficacy of Oral Ribavirin in Lung Transplant Patients With Respiratory Syncytial Virus Lower Respiratory Tract Infection

BACKGROUND Respiratory syncytial virus (RSV) can cause severe lower respiratory tract infection (LRI) and is a risk factor for the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Currently, the most widely used therapy for RSV is inhaled ribavirin. However, this therapy is costly and cumbersome. We investigated the utility of using oral ribavirin for the treatment of RSV infection after LTx. METHODS RSV was identified in nasopharyngeal swabs (NPS) or bronchoalveolar lavage (BAL) using direct fluorescent antibody (DFA) in 5 symptomatic LTx patients diagnosed with LRI. Data were collected from December 2005 and August 2007 and included: age; gender; type of LTx; underlying disease; date of RSV; pulmonary function prior to, during and up to 565 days post-RSV infection; need for mechanical ventilation; concurrent infections; and radiographic features. Patients received oral ribavirin for 10 days with solumedrol (10 to 15 mg/kg/day intravenously) for 3 days, until repeat NPS were negative. RESULTS Five patients had their RSV-LRI diagnosis made at a median of 300 days post-LTx. Mean forced expiratory volume in 1 second (FEV(1)) fell 21% (p < 0.012) during infection. After treatment, FEV(1) returned to baseline and was maintained at follow-up of 565 days. There were no complications and no deaths with oral therapy. A 10-day course of oral ribavirin cost

Predisposition for disrepair in the aged lung.

700 compared with

Bilateral Lung Transplantation Offers Better Long-Term Survival, Compared With Single-Lung Transplantation, for Younger Patients With Idiopathic Pulmonary Fibrosis

14,000 for nebulized ribavirin at 6 g/day. CONCLUSIONS Treatment of RSV after LTx with oral ribavirin and corticosteroids is well tolerated, effective and less costly than inhaled ribavirin. Further studies are needed to directly compare the long-term efficacy of oral vs nebulized therapy for RSV.

Receptor for Advanced Glycation End Products in Donor Lungs Is Associated with Primary Graft Dysfunction After Lung Transplantation

Introduction: Idiopathic pulmonary fibrosis (IPF) is a devastating progressive lung disease with an average survival of only 3 to 5 years. The mechanisms underlying the initiation and progression of IPF are poorly understood, and treatments available have only modest effect on disease progression. Interestingly, the incidence of IPF is approximately 60 times more common in individuals aged 75 years and older, but the mechanism by which aging promotes fibrosis is unclear. The authors hypothesized that aged lungs have a profibrotic phenotype that render it susceptible to disrepair after injury. Methods: Young and old mice were treated with bleomycin to examine disrepair in the aged lung. In addition, uninjured young and old mouse lungs were analyzed for transforming growth factor-beta 1 (TGF-&bgr;1) production, extracellular matrix composition and lung fibroblast phenotype. Lung fibroblasts were treated with a DNA methyltransferase inhibitor to examine the potential epigenetic mechanisms involved in age-associated phenotypic alterations. Results: The lungs of old mice showed worse fibrosis after bleomycin-induced injury compared with the lungs from young mice. At baseline, aged lungs expressed a profibrotic phenotype characterized by increased mRNA expression for fibronectin extracellular domain A (Fn-EDA) and the matrix metalloproteinases (MMPs) MMP-2 and MMP-9. Old lungs also expressed higher levels of TGF-&bgr; receptor 1 and TGF-&bgr;1 mRNA, protein and activity as determined by increased Smad3 expression, protein phosphorylation and DNA binding. Lung fibroblasts harvested from aged lungs showed reduced expression of the surface molecule Thy-1, a finding also implicated in lung fibrosis; the latter did not seem related to Thy-1 gene methylation. Conclusion: Altogether, aged lungs manifest a profibrotic phenotype characterized by enhanced fibronectin extracellular domain A and MMP expression and increased TGF-&bgr;1 expression and signaling and are populated by Thy-1–negative fibroblasts, all implicated in the pathogenesis of lung fibrosis.

Attenuation of Early Airway Obstruction by Mesenchymal Stem Cells in a Murine Model of Heterotopic Tracheal Transplantation

BACKGROUND Single-lung transplantation (SLT) and bilateral lung transplantation (BLT) are both good options for patients with end-stage lung disease secondary to idiopathic pulmonary fibrosis. It is, however, unclear whether BLT offers any survival advantage over SLT. The purpose of our study was to evaluate a large group of patients to determine if either SLT or BLT officered a long-term survival advantage for patients with IPF. METHODS This was an Institutional Review Board-approved retrospective analysis of the United Network of Organ Sharing database from 1987 to 2008. Survival was determined using Kaplan-Meir estimates and the effect of laterality was determined by Cox proportional hazards and propensity analyses. RESULTS Lung transplantation for idiopathic pulmonary fibrosis was performed in 3,860 patients (2,431 SLTs and 1429 BLTs). Multivariate and propensity analysis failed to show any survival advantage for BLT (hazard ratio = 0.90, 95% confidence interval = 0.78 to 1.0, p = 0.11). One-year conditional survival favored BLT (hazard ratio 0.73, 95% confidence interval 0.60 to 0.87, p = 0.00064). Risk factors for early death included recipient age over 57 and donor age over 36 years. CONCLUSIONS Bilateral lung transplantation should be considered for younger patients with idiopathic pulmonary fibrosis and results may be optimized when younger donors are used.

Effect of bone marrow-derived mesenchymal stem cells on endotoxin-induced oxidation of plasma cysteine and glutathione in mice.

Development of primary graft dysfunction (PGD) is associated with poor outcomes after transplantation. We hypothesized that Receptor for Advanced Glycation End‐products (RAGE) levels in donor lungs is associated with the development of PGD. Furthermore, we hypothesized that RAGE levels would be increased with PGD in recipients after transplantation. We measured RAGE in bronchoalveolar lavage fluid (BALf) from 25 donors and 34 recipients. RAGE was also detected in biopsies (transbronchial biopsy) from recipients with and without PGD. RAGE levels were significantly higher in donor lungs that subsequently developed sustained PGD versus transplanted lungs that did not display PGD. Donor RAGE level was a predictor of recipient PGD (odds ratio = 1.768 per 0.25 ng/mL increase in donor RAGE level). In addition, RAGE levels remained high for 14 days in those recipients that developed severe graft dysfunction. Recipients may be at higher risk for developing PGD if they receive transplanted organs that have higher levels of soluble RAGE prior to explantation. Moreover, the clinical and pathologic abnormalities associated with PGD posttransplantation are associated with increased RAGE expression. These findings also raise the possibility that targeting the RAGE signaling pathway could be a novel strategy for treatment and/or prevention of PGD.

Gastroesophageal Reflux Disease Is Associated With an Increased Rate of Acute Rejection in Lung Transplant Allografts

BACKGROUND Long-term success in lung transplantation is limited by obliterative bronchiolitis (OB). Presently, complete understanding of the mechanisms of OB has been elusive. Bone marrow-derived mesenchymal stem cells (MSC) have been shown to modulate repair of the injured lung in multiple disease models. We hypothesized that the injection of MSC would prevent development of early airway obstruction (AO) in the heterotopic tracheal transplant model. METHODS Forty-four tracheas from BALB/c and C57BL/6 donors were transplanted into 22 C57BL/6 recipients. At the time of transplant, 13 of the allogeneic recipient mice were injected with 5 × 10(5) MSC from various murine sources. To confirm the role of the immune response in the generation of AO we used a permeable inhibitor of nuclear factor-kappaB (NF-κB) in 11 recipients after transplantation with 22 BALB/c tracheas. RESULTS After transplantation, administration of MSC inhibited intraluminal obstruction by collagen in 98% of the mice and transforming factor-beta (TGF-β) expression decreased to levels similar to those observed in isograft controls. These effects were associated with a significant (p < 0.05) increase in expression of the anti-inflammatory cytokine interleukin-10 (IL-10). NF-κB inhibitor showed decreased expression of transforming growth factor-beta (TGF-β) in the Day 7 and Day 14 groups, resulting in a 60% reduction of luminal obstruction as well as a decrease in inflammatory cells to the airway. CONCLUSION Our observations suggest that administration of MSC prevents development of airway occlusion in a mouse model, probably through the modulated immune response altering TGF-β expression.

Dynamics of Human Regulatory T Cells in Lung Lavages of Lung Transplant Recipients

Bone marrow-derived mesenchymal stem cells (BMDMSC) are emerging as a therapeutic modality in various inflammatory disease states, including acute lung injury (ALI). A hallmark of inflammation, and a consistent observation in patients with ALI, is a perturbation in the systemic redox environment. However, little is known about the effects of BMDMSC on the systemic redox status. The objective of the present study was to determine whether exogenously infused BMDMSC protect against endotoxin-induced oxidation of plasma cysteine (Cys) and glutathione (GSH) redox states. To determine the effect on the redox state if BMDMSC, mice received endotoxin intraperitoneally (1 mg/kg), followed by intravenous infusion of either 5 × 105 BMDMSC or an equal volume of saline solution. Control mice received intraperitoneal endotoxin followed by 5 × 105 lung fibroblasts given intravenously. Cys, cystine (CySS), GSH, and glutathione disulfide (GSSG) concentrations were determined by HPLC. Results showed sequential preservation of plasma Cys and GSH levels in response to BMDMSC infusion. The data show that BMDMSC infusion leads to a more reducing Cys and GSH redox state. The findings are the first to demonstrate that BMDMSC have antioxidant effects in vivo, and add to our understanding of the systemic effects of BMDMSC in lung injury.

Dapsone-induced Hemolytic Anemia in Lung Allograft Recipients

PURPOSE Gastric fundoplication (GF) for gastroesophageal reflux disease (GERD) may protect against the progression of chronic rejection in lung transplant (LT) recipients. However, the association of GERD with acute rejection episodes (ARE) is uncertain. This study sought to identify if ARE were linked to GERD in LT patients. METHODS This single-center retrospective observational study, of patients transplanted from January 1, 2000, to January 31, 2009, correlated results of pH probe testing for GERD with ARE (≥International Society for Heart and Lung Transplantation A1 or B1). We compared the rates of ARE among patients with GERD (DeMeester Score > 14.7) versus without GERD as number of ARE per 1,000 patient-days after LT. Patients undergoing GF prior to LT were excluded. RESULTS The analysis included 60 LT subjects and 9,249 patient-days: 33 with GERD versus 27 without GERD. We observed 51 ARE among 60 LT recipients. The rate of ARE was highest among patients with GERD: 8.49 versus 2.58, an incidence density ratio (IDR) of 3.29 (P = .00016). Upon multivariate negative binomial regression modeling, only GERD was associated with ARE (IDR 2.15; P = .009). Furthermore, GERD was associated with multiple ARE (36.4% vs 0%; P < .0001) and earlier onset compared with patients without GERD: ARE proportion at 2 months was 0.55 versus 0.26 P = .004). CONCLUSION In LT recipients, GERD was associated with a higher rate, multiple events, and earlier onset of ARE. The efficacy of GF to reduce ARE among patients with GERD needs further evaluation.

Bile Acid Aspiration Associated With Lung Chemical Profile Linked to Other Biomarkers of Injury After Lung Transplantation

Background. Despite advances in the field of lung transplantation, the median survival after lung transplant remains below 5 years. Early rejection is a risk factor for the development of chronic rejection. In animal models of transplant tolerance, regulatory T cells (Tregs) can prevent the establishment of rejection. Methods. This study was designed to explore the dynamics of Tregs focally and systemically in lung transplant recipients. Sequential surveillance bronchoscopy results were available in 51 patients with at least four sequential samples recovered from each patient at defined times posttransplant. In 36 individuals, a complete year of follow-up data for BAL was analyzed. In 33 of these individuals had a complete year of follow-up data for peripheral blood monocyte cell specimens were also analyzed. Lung lavage cells were recovered from each bronchoscopy and corresponding blood draw and subjected to polychromatic flow cytometry. The percentage of CD4 lymphocytes, which expressed the intracellular transcription factor FoxP3 was recorded at each point. At each time point, lung biopsy specimens were scored for rejection. Results. Lung Treg frequency was significantly more variable than blood Treg frequency. Treg frequency in the lung was increased in the aftermath of acute rejection. In contrast, lung Treg frequency declined sequentially in patients demonstrating continued quiescence. Mean BAL Treg level integrated over the first transplant year correlated inversely with the degree of acute cellular rejection. In contrast, blood Treg levels demonstrated no correlation with lung pathology. Conclusions. Lung Tregs increase in the setting of acute cellular rejection, whereas declining levels of BAL Tregs correlates with immunologic quiescence.