Gordon L. Yung

Extended Valganciclovir Prophylaxis to Prevent Cytomegalovirus After Lung Transplantation: A Randomized, Controlled Trial

BACKGROUND Cytomegalovirus (CMV) is the most prevalent opportunistic infection after lung transplantation. Current strategies do not prevent CMV in most at-risk patients. OBJECTIVE To determine whether extending prophylaxis with oral valganciclovir from the standard 3 months to 12 months after lung transplantation is efficacious. DESIGN Randomized, clinical trial. Patients were randomly assigned by a central automated system to treatment or placebo. Patients and investigators were blinded to treatment status. (ClinicalTrials.gov registration number: NCT00227370) SETTING Multicenter trial involving 11 U.S. lung transplant centers. PATIENTS 136 lung transplant recipients who completed 3 months of valganciclovir prophylaxis. INTERVENTION 9 additional months of oral valganciclovir (n = 70) or placebo (n = 66). MEASUREMENTS The primary end point was freedom from CMV disease (syndrome or tissue-invasive) on an intention-to-treat basis 300 days after randomization. Secondary end points were CMV disease severity, CMV infection, acute rejection, opportunistic infections, ganciclovir resistance, and safety. RESULTS CMV disease occurred in 32% of the short-course group versus 4% of the extended-course group (P < 0.001). Significant reductions were observed with CMV infection (64% vs. 10%; P < 0.001) and disease severity (110 000 vs. 3200 copies/mL, P = 0.009) with extended treatment. Rates of acute rejection, opportunistic infections, adverse events, CMV UL97 ganciclovir-resistance mutations, and laboratory abnormalities were similar between groups. During the 6 months after study completion, a low incidence of CMV disease was observed in both groups. LIMITATION Longer-term effects of extended prophylaxis were not assessed. CONCLUSION In adult lung transplant recipients who have received 3 months of valganciclovir, extending prophylaxis by an additional 9 months significantly reduces CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity. A beneficial effect with regard to prevention of CMV disease seems to extend at least through 18 months after transplantation.

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point http://ow.ly/p0RDL

PULMONARY VASCULAR REMODELING DISTAL TO PULMONARY ARTERY LIGATION IS ACCOMPANIED BY UPREGULATION OF ENDOTHELIN RECEPTORS AND NITRIC OXIDE SYNTHASE

There is increasing evidence that the pathogenesis and progression of many forms of pulmonary vasculopathy are related to abnormalities in endothelial mediators, including endothelin-1 (ET-1) and nitric oxide (NO). Using a rat model of chronic unilateral pulmonary artery ligation, we investigated the role of ET-1 and NO in postobstructive pulmonary vasculopathy (POPV). Eight months after a left thoracotomy with either left main pulmonary artery ligation (ligated group) or no ligation (sham group), rat lungs, including those contralateral to the ligation (hyperperfused group), were fixed and mounted for histologic sectioning. Morphometric measurements were carried out by computer-assisted image analysis and immunohistochemical staining was performed using specific antibodies against ET-1, ETA, and EBB receptors, and endothelial NO synthase (eNOS). Compared to sham lungs, the ligated lungs showed (1) an increase in muscular, adventitial, and intimal thickness of pulmonary artery; (2) increase in external diameter of the bronchial artery (39.8 +/- 2.2 microns vs. 16.8 +/- 0.9 microns in sham group; P < .005) and number of bronchial arteries per bronchiole (3.21 +/- mu 0.26 vs. 1.86 +/- mu 0.21 in sham group; P < .001); and (3) increase in the intensity of eNOS and ETA, B receptor immunoreactivity. No morphometric or immunohistochemical differences were observed between the hyperperfused and sham lungs. These findings suggest that increased synthesis of endothelial NO may serve as a compensatory mediator in ET-1-mediated vascular remodeling.There is increasing evidence that the pathogenesis and progression of many forms of pulmonary vasculopathy are related to abnormalities in endothelial mediators, including endothelin-1 (ET-1) and nitric oxide (NO). Using a rat model of chronic unilateral pulmonary artery ligation, we investigated the role of ET-1 and NO in postobstructive pulmonary vasculopathy (POPV). Eight months after a left thoracotomy with either left main pulmonary artery ligation (ligated group) or no ligation (sham group), rat lungs, including those contralateral to the ligation (hyperperfused group), were fixed and mounted for histologic sectioning. Morphometric measurements were carried out by computer-assisted image analysis and immunohistochemical staining was performed using specific antibodies against ET-1, ETA, and EBB receptors, and endothelial NO synthase (eNOS). Compared to sham lungs, the ligated lungs showed (1) an increase in muscular, adventitial, and intimal thickness of pulmonary artery; (2) increase in external diameter of the bronchial artery (39.8+/-2.2 mum vs.16.8+/-0.9 mum in sham group; P <. 005) and number of bronchial arteries per bronchiole (3.21+/-mu0.26vs.1.86+/-mu0.21 in sham group; P <. 001); and (3) increase in the intensity of eNOS and ETA, B receptor immunoreactivity. No morphometric or immunohistochemical differences were observed between the hyperperfused and sham lungs. These ndings suggest that increased synthesis of endothelial NO may serve as a compensatory mediator in ET-1 mediated vascular remodeling.

Donor transfer of pulmonary coccidioidomycosis in lung transplantation

Transplant recipients living in endemic areas are at high risk of aerosol-transmitted fungal infections because of environmental exposure while on immunosuppressive drugs, as well as reactivation of latent infection from either the patients or the donors organs. The latter may account for early development of coccidioidomycosis after transplantation. We describe a case of pulmonary coccidioidomycosis in a lung transplant recipient who acquired the infection from the donor lung and presented with fulminant pneumonia in the immediate postoperative period.

Increased incidence of cutaneous squamous cell carcinoma in lung transplant recipients taking long-term voriconazole

BACKGROUND Voriconazole has been used for prevention and treatment of fungal infections in patients after lung transplantation. We postulate that long-term use of voriconazole may increase the risk of squamous cell carcinoma of the skin in these patients. METHODS The study included 120 patients who received lung transplantation at UC San Diego Health System between July 2000 and June 2006. All patients received a similar initial immunosuppression regimen, and 43 (35.8%) received voriconazole for treatment or prophylaxis for fungal diseases. In this retrospective study, we compared the incidence of squamous cell carcinoma in lung transplant recipients with or without voriconazole use. RESULTS Squamous cell carcinomas developed in 39.5% of patients (17 of 43) who received voriconazole for prophylaxis or treatment of fungal disease, compared with 19.5% (15 of 77) who did not receive voriconazole (p = 0.03). Four patients died of metastatic squamous cell carcinoma, all in the voriconazole group. Multiple logistic regression analysis showed older age at the time of transplant (odds ratio [OR], OR (95% CI) 2.8 (1.5-5.5)), skin cancer pre-transplant (OR, 11.0 (1.76-68.4), and longer voriconazole therapy (OR, 1.8 (1.3-2.6)) were independent risk factors for development of skin cancer after transplant. CONCLUSIONS Our results suggest that long-term use of voriconazole may be associated with development of cutaneous squamous cell carcinoma in patients after lung transplant. Greater clinical aggressiveness of skin cancer was also noted in these patients.

Airway stenoses after lung transplantation: Incidence, management, and outcome

OBJECTIVE Airway stenoses have been a significant cause of morbidity and mortality after lung transplantation. We reviewed our 11-year experience with dilatation and silicone stent treatment of airway strictures after lung transplantation. We adopted this approach after managing the complications of nitinol/wire mesh stents, including stent fracture, granulation tissue overgrowth, and difficulty with removal. METHODS Between January of 1996 and December of 2007, 240 patients underwent lung transplantation (132 single lung, 108 double lung; 121 male, 119 female; mean age 49.4 +/- 12.9 years). Twenty patients (8.3%) developed >50% stenosis in 22 airways over 35 to 135 days following surgery. Short and long-segment strictures were managed with rigid bronchoscopy, mechanical/laser debridement, balloon dilatation, and silicone stent placement. Mean follow-up was 4.9 +/- 3.5 years after stent removal. RESULTS The mean time to diagnosis of airway stenosis was 81.5 +/- 26.9 days. Pulmonary aspergillosis and pseudomonal infection, age less than 45 years, and early rejection correlated with airway stenosis; however, ischemic time, side of transplant, and preoperative disease did not. Airway patency and symptom improvement were achieved in 18 of 20 patients. Sixteen patients were able to have their stents removed at a mean of 362.3 +/- 126.4 days with permanent resolution of airway stenosis. Overall survival was similar for patients with and without airway stenosis. CONCLUSION Airway stenosis after lung transplantation can be successfully managed with bronchoscopic dilatation and temporary silicone stent placement. With time, most short and long airway stenoses resolve with atraumatic stenting of the affected areas. Removal of stents with permanent airway patency is achievable in most lung transplant recipients with airway stenosis.

Outpatient inhaled nitric oxide in a patient with idiopathic pulmonary fibrosis: a bridge to lung transplantation ☆

Inhaled nitric oxide (INO) has been shown to improve oxygenation and decrease intrapulmonary shunt and pulmonary hypertension in various lung diseases. In this study we report a patient with end-stage idiopathic pulmonary fibrosis and pulmonary hypertension who received INO after coronary artery bypass surgery, with significant improvement in arterial oxygenation and pulmonary arterial pressure. Using a pulsing delivery system, the patient continued to receive outpatient INO for 30 months while waiting for lung transplantation. Exercise study and two-dimensional echocardiogram, after 3 months of inhaled NO, demonstrated continued benefits of INO for improvement of arterial oxygenation, pulmonary arterial pressure and exercise tolerance.

Severe alveolar proteinosis following chemotherapy for acute myeloid leukemia in a lung allograft recipient

A 64-year-old man was diagnosed with acute myeloid leukemia (AML) 5 years following single lung transplantation performed for severe pulmonary hypertension from scleroderma. Chemotherapy for treatment of AML with fludarabine, cytosine arabinoside, G-CSF (FLAG) regimen was initiated. Despite intensive antibiotic treatment for a presumptive diagnosis of bacterial pneumonia, the patient developed acute respiratory failure and died before a complete cycle of chemotherapy could be administered. At autopsy, both native and allograft lungs showed widespread alveolar proteinosis that was determined as the main cause of acute respiratory failure. Alveolar proteinosis, a potentially treatable disease, should be considered in the radiologic differential diagnosis of diffuse lung disease in this clinical setting.

Lung Transplantation and Pulmonary Hypertension

The presence of pulmonary hypertension affects lung transplantation in multiple ways, from patient selection, transplant risks, type of transplant, intraoperative management, to transplant outcome. A working knowledge of natural disease progression, the latest medical treatment options, and transplant outcome is critical in patient selection, and a good understanding of the transplant process, including the new transplant allocation system, is important for physicians involved in the care of patients with pulmonary arterial hypertension. The complexity of these factors underscores the importance of good communication between referring physicians and transplant centers.

Lung transplantation and extracorporeal photopheresis: The answer to bronchiolitis obliterans?

Bronchiolitis obliterans (BO) is a rare condition characterized by narrowing of small airways. Although it can be caused by variety of conditions, most cases occur after lung and bone marrow transplantation in the form of graft-versus-host-disease and chronic rejection, respectively. Extracorporeal photopheresis (ECP) has emerged as a promising treatment for the condition, especially for BO after lung transplantation. Available data suggest that around two-thirds of patients may demonstrate either slowing or cessation of disease progression after treatment with ECP. Recent researches also provide interesting insights into possible mechanism of action of ECP in BO.