Kevin M. Chan

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.

Lung transplantation in the United States, 1998-2007.

This article highlights trends and changes in lung and heart‐lung transplantation in the United States from 1998 to 2007. The most significant change over the last decade was implementation of the Lung Allocation Score (LAS) allocation system in May 2005. Subsequently, the number of active wait‐listed lung candidates declined 54% from pre‐LAS (2004) levels to the end of 2007; there was also a reduction in median waiting time, from 792 days in 2004 to 141 days in 2007. The number of lung transplants performed yearly increased through the decade to a peak of 1 465 in 2007; the greatest single year increase occurred in 2005. Despite candidates with increasingly higher LAS scores being transplanted in the LAS era, recipient death rates have remained relatively stable since 2003 and better than in previous years. Idiopathic pulmonary fibrosis became the most common diagnosis group to receive a lung transplant in 2007 while emphysema was the most common diagnosis in previous years. The number of retransplants and transplants in those aged ≥65 performed yearly have increased significantly since 1998, up 295% and 643%, respectively. A decreasing percentage of lung transplant recipients are children (3.5% in 2007, n = 51). With LAS refinement ongoing, monitoring of future impact is warranted.

An Official American Thoracic Society/International Society for Heart and Lung Transplantation/Society of Critical Care Medicine/Association of Organ and Procurement Organizations/United Network of Organ Sharing Statement: Ethical and Policy Considerations in Organ Donation after Circulatory Determination of Death

RATIONALE Donation after circulatory determination of death (DCDD) has the potential to increase the number of organs available for transplantation. Because consent and management of potential donors must occur before death, DCDD raises unique ethical and policy issues. OBJECTIVES To develop an ethics and health policy statement on adult and pediatric DCDD relevant to critical care and transplantation stakeholders. METHODS A multidisciplinary panel of stakeholders was convened to develop an ethics and health policy statement. The panel consisted of representatives from the American Thoracic Society, Society of Critical Care Medicine, International Society for Heart and Lung Transplantation, Association of Organ Procurement Organizations, and the United Network of Organ Sharing. The panel reviewed the literature, discussed important ethics and health policy considerations, and developed a guiding framework for decision making by stakeholders. RESULTS A framework to guide ethics and health policy statement was established, which addressed the consent process, pre- and post mortem interventions, the determination of death, provisions of end-of-life care, and pediatric DCDD. CONCLUSIONS The information presented in this Statement is based on the current evidence, experience, and clinical rationale. New clinical research and the development and dissemination of new technologies will eventually necessitate an update of this Statement.

Efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid-organ transplant recipients with invasive fungal infections

Background: Fungal infections following solid‐organ transplantation are a major source of morbidity and mortality. This report describes the efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid‐organ transplant recipients. 
Methods: Three open‐label, second‐line treatment studies evaluated ABLC as a treatment for severe, life‐threatening mycoses in patients who were refractory to or intolerant to conventional antifungal (mostly amphotericin B [AmB]) therapy or had pre‐existing renal disease. 
Results: The 79 solid‐organ transplant recipients (25 heart, 20 liver, 17 kidney, 11 lung, 5 multiple, 1 pancreas) who received ABLC in these studies had the following fungal infections: aspergillosis (n=39); candidiasis (n=20); zygomycosis (n=8); cryptococcosis and histoplasmosis (n=3 each); and blastomycosis, cladosporiosis, fusariosis, Bipolaris hawaiiensis, Dactylaria gallopava, and an unspecified fungal infection (n=1 each). The median duration of ABLC therapy was 28 d (1–178 d). The daily dose ranged between 1.6 and 7.4 mg/kg (median, 4.6 mg/kg). The clinical response rate for the patients who could be assessed was 58% (39/67). Clinical response rates for heart, liver, kidney, and lung recipients were 59, 60, 67, and 40%, respectively; response rates for aspergillosis and candidiasis were 47 and 71%, respectively. Forty‐six of the 79 patients (58%) survived for more than 28 d after the last dose of ABLC. Mean baseline serum creatinine was 3.2 mg/dL; 64 patients (81%) had stable (n=37) or improved (n=27) serum creatinine at the end of treatment. 
Conclusions: ABLC is safe and effective treatment for fungal infections in solid‐organ transplant recipients. Its renal‐sparing properties are particularly suited for this high‐risk population for renal failure.

Mesenchymal Stromal Cells in Bronchoalveolar Lavage as Predictors of Bronchiolitis Obliterans Syndrome

RATIONALE Bronchoalveolar lavage fluid (BAL) from human lung allografts demonstrates the presence of a multipotent mesenchymal stromal cell population. However, the clinical relevance of this novel cellular component of BAL and its association with bronchiolitis obliterans syndrome (BOS), a disease marked by progressive airflow limitation secondary to fibrotic obliteration of the small airways, remains to be determined. OBJECTIVES In this study we investigate the association of number of mesenchymal stromal cells in BAL with development of BOS in human lung transplant recipients. METHODS Mesenchymal colony-forming units (CFUs) were quantitated in a cohort of 405 BAL samples obtained from 162 lung transplant recipients. Poisson generalized estimating equations were used to determine the predictors of BAL mesenchymal CFU count. MEASUREMENTS AND MAIN RESULTS Higher CFU counts were noted early post-transplantation; time from transplant to BAL of greater than 3 months predicted 0.4-fold lower CFU counts (P = 0.0001). BOS diagnosis less than or equal to 365 days before BAL was associated with a 2.11-fold higher CFU count (P = 0.02). There were 2.62- and 2.70-fold higher CFU counts noted in the presence of histologic diagnosis of bronchiolitis obliterans (P = 0.05) and organizing pneumonia (0.0003), respectively. In BAL samples obtained from BOS-free patients greater than 6 months post-transplantation (n = 173), higher mesenchymal CFU counts (≥10) significantly predicted BOS onset in both univariate (hazard ratio, 5.61; 95% CI, 3.03-10.38; P < 0.0001) and multivariate (hazard ratio, 5.02; 95% CI, 2.40-10.51; P < 0.0001) Cox regression analysis. CONCLUSIONS Measurement of mesenchymal CFUs in the BAL provides predictive information regarding future BOS onset.

The HCAP Gap: Differences between Self-Reported Practice Patterns and Published Guidelines for Health Care-Associated Pneumonia

BACKGROUND Health care-associated pneumonia (HCAP) is prevalent among hospitalized patients. In contrast to community-acquired pneumonia (CAP), patients with HCAP are at increased risk for multidrug-resistant organisms, and appropriate initial antibiotic therapy is associated with reduced mortality. METHODS An online survey was distributed to faculty and housestaff at 4 academic medical centers. The survey required respondents to choose initial antibiotic therapy for 9 hypothetical pneumonia cases (7 cases of HCAP and 2 cases of CAP). Answers were considered correct if the antibiotic regimen chosen was consistent with published guidelines. In addition, physicians rated their knowledge of current guidelines, as well as their level of agreement with guideline recommendations. RESULTS Surveys were sent to 1313 physicians with a response rate of 65% (n = 855). Respondents included physicians in the following categories: hospital medicine/internal medicine, 60%; emergency medicine, 25%; and critical care, 13%. Respondents selected guideline-concordant antibiotic regimens 78% of the time for CAP, but only 9% of the time for HCAP. Because mean scores for HCAP questions were extremely low (mean, 0.63 correct answers out of 7), differences in performance between groups were too small to be meaningful. Despite their poor performance, 71% of the respondents stated that they are aware of published guidelines for HCAP, and 79% stated that they agree with and practice according to the guidelines. CONCLUSIONS In this survey, physicians reported they were aware of, agreed with, and practiced according to published pneumonia guidelines; however, the overwhelming majority did not choose guideline-concordant therapy when tested.

Bacteremia in Lung Transplant Recipients in the Current Era

Current trends in the epidemiology, outcome and variables influencing mortality in bacteremic lung transplant recipients have not been fully described. We prospectively studied bacteremias in lung transplant recipients in a multicenter study between 2000–2004. Bacteremia was documented in 56 lung transplant recipients, an average of 172 days after transplantation. Multiple antibiotic resistance was documented in 48% of the isolates; these included 57% of the Gram‐negative and 38% of the Gram‐positive bacteria. Pulmonary infection was the most common source of resistant gram‐negative bacteremias. Mortality rate at 28 days after the onset of bacteremia was 25% (14/56). Mechanical ventilation and abnormal mental status correlated independently with higher mortality (p < 0.05 for both variables). Bacteremia remains a significant complication in lung transplant recipients and is associated with considerable mortality. Recognition of variables portending a high risk for antibiotic resistance and for poor outcome has implications relevant for optimizing antibiotic prescription and for improving outcomes in lung transplant recipients.

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

OBJECTIVES Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and inflammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents. METHODS Committee members developed and refined a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline. CONCLUSIONS It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease.

Bronchogenic carcinoma in lung transplant recipients

Although lung transplant recipients have a higher prevalence of non-melanoma skin cancers and lymphoma than the general population, the same has not been noted for bronchogenic carcinoma. If an increased prevalence of bronchogenic carcinoma exists, contributing factors may include the high rate of previous tobacco use in this population and/or the chronic immunosuppression used to prevent allograft rejection. With time, the incidence of bronchogenic carcinoma in the lung transplant population is likely to parallel the increasing longevity and number of transplanted individuals. We describe 2 cases of bronchogenic carcinoma in lung transplant recipients that demonstrate the morbidity associated with the discovery or development of bronchogenic carcinoma in this population.

Noninfectious pulmonary complications after organ transplantation

Organ transplantation is a successful and recognized option for patients with end-stage pulmonary, cardiac, hepatic, renal, and hematologic disease. As with any new technology, however, a set of complications has developed in the form of lung injury after transplantation as a result of ischemic, chemotherapeutic, radiation-induced, and immunologic damage to the lungs. Interstitial changes soon after transplantation are typically due to pulmonary edema, the adult respiratory distress syndrome, and reperfusion injury or allograft rejection (in the case of lung transplantation). Late pulmonary injury presents as obliterative bronchiolitis and lymphoproliferative disease. Bone marrow transplant recipients are unique because they develop the idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, pulmonary venoocclusive disease, and graft-versus-host disease. New insights about these interstitial syndromes are the subject of this review.