The Lung Allocation Score and Its Relevance.

Lung transplantation in the United States, under oversight by the Organ Procurement Transplantation Network (OPTN) in the 1990s, operated under a system of allocation based on location within geographic donor service areas, wait time of potential recipients, and ABO compatibility. On May 4, 2005, the lung allocation score (LAS) was implemented by the OPTN Thoracic Organ Transplantation Committee to prioritize patients on the wait list based on a balance of wait list mortality and posttransplant survival, thus eliminating time on the wait list as a factor of prioritization. Patients were categorized into four main disease categories labeled group A (obstructive lung disease), B (pulmonary hypertension), C (cystic fibrosis), and D (restrictive lung disease/interstitial lung disease) with variables within each group impacting the calculation of the LAS. Implementation of the LAS led to a decrease in the number of wait list deaths without an increase in 1-year posttransplant survival. LAS adjustments through the addition, modification or elimination of covariates to improve the estimates of patient severity of illness, have since been made in addition to establishing criteria for LAS value exceptions for pulmonary hypertension patients. Despite the success of the LAS, concerns about the prioritization, and transplantation of older, sicker individuals have made some aspects of the LAS controversial. Future changes in US lung allocation are anticipated with the current development of a continuous distribution model that incorporates the LAS, geographic distribution, and unaccounted aspects of organ allocation into an integrated score.

Extracorporeal photopheresis to attenuate decline in lung function due to refractory obstructive allograft dysfunction.

BACKGROUND: This study was designed to prospectively evaluate the efficacy of extracorporeal photopheresis (ECP) to attenuate the rate of decline of FEV1 in lung transplant recipients with refractory bronchiolitis obliterans. Due to an observed higher than expected early mortality, a preliminary analysis was performed. STUDY DESIGN AND METHODS: Subjects from 10 lung transplant centres were assigned to ECP treatment or to observation based on spirometric criteria, with potential crossover for those under observation. The primary endpoint of this study was to assess response to ECP (i.e., greater than a 50% decrease in the rate of FEV1 decline) before and 6 months after initiation of ECP. Mortality was also evaluated 6 and 12 months after enrolment as a secondary endpoint. RESULTS: Of 44 enrolled subjects, 31 were assigned to ECP treatment while 13 were initially assigned to observation on a non-random basis using specific spirometric inclusion criteria (seven of the observation patients subsequently crossed over to receive ECP). Of evaluable patients, 95% of patients initially assigned to treatment responded to ECP with rates of FEV1 decline that were reduced by 93% in evaluable ECP-treated patients. Mortality rates (percentages) at 6 and 12 months after enrolment was 32% and 41%, respectively. The most common (92%) primary cause of death was respiratory or graft failure. Significantly (p = 0.002) higher rates of FEV1 decline were observed in the non-survivors (-212 ± 177 ml/month) when compared to the survivors (-95 ± 117 ml/month) 12 months after enrolment. In addition, 18 patients with bronchiolitis obliterans syndrome (BOS) diagnosis within 6 months of enrolment had lost 38% of their baseline lung function at BOS diagnosis and 50% of their lung function at enrolment. CONCLUSIONS: These analyses suggest that earlier detection and treatment of BOS should be considered to appreciate improved outcomes with ECP.

Mechanistic Target of Rapamycin Complex 1 (mTORC1) and mTORC2 as Key Signaling Intermediates in Mesenchymal Cell Activation.

Fibrotic diseases display mesenchymal cell (MC) activation with pathologic deposition of matrix proteins such as collagen. Here we investigate the role of mTOR complex 1 (mTORC1) and mTORC2 in regulating MC collagen expression, a hallmark of fibrotic disease. Relative to normal MCs (non-Fib MCs), MCs derived from fibrotic human lung allografts (Fib-MCs) demonstrated increased phosphoinositide-3kinase (PI3K) dependent activation of both mTORC1 and mTORC2, as measured by increased phosphorylation of S6K1 and 4E-BP1 (mTORC1 substrates) and AKT (an mTORC2 substrate). Dual ATP-competitive TORC1/2 inhibitor AZD8055, in contrast to allosteric mTORC1-specific inhibitor rapamycin, strongly inhibited 4E-BP1 phosphorylation and collagen I expression in Fib-MCs. In non-Fib MCs, increased mTORC1 signaling was shown to augment collagen I expression. mTORC1/4E-BP1 pathway was identified as an important driver of collagen I expression in Fib-MCs in experiments utilizing raptor gene silencing and overexpression of dominant-inhibitory 4E-BP1. Furthermore, siRNA-mediated knockdown of rictor, an mTORC2 partner protein, reduced mTORC1 substrate phosphorylation and collagen expression in Fib-, but not non-Fib MCs, revealing a dependence of mTORC1 signaling on mTORC2 function in activated MCs. Together these studies suggest a novel paradigm where fibrotic activation in MCs increases PI3K dependent mTORC1 and mTORC2 signaling and leads to increased collagen I expression via the mTORC1-dependent 4E-BP1/eIF4E pathway. These data provide rationale for targeting specific components of mTORC pathways in fibrotic states and underscore the need to further delineate mTORC2 signaling in activated cell states.

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.

Lung transplantation across donor-specific anti-human leukocyte antigen antibodies: utility of bortezomib therapy in early graft dysfunction.

OBJECTIVE: To report the usefulness of bortezomib therapy in a sensitized lung transplant recipient experiencing antibody-mediated rejection. CASE SUMMARY: During a pretransplant evaluation, a 62-year-old woman with usual interstitial pneumonitis developed a diverticular bleed requiring transfusions, which elevated her panel reactive antibody to 98% for human leukocyte antigen (HLA) class I and 71% for class II. She underwent desensitization to decrease her panel reactive antibody levels. She received a double lung transplant across a weak HLA class II incompatibility but developed respiratory failure due to early graft dysfunction. On postoperative day (POD) 14 she was found to have donor-specific antibodies (DSA) to HLA class I and class II antigens. She received intravenous immunoglobulin (IVIG), plasmapheresis, and bortezomib to reduce the DSA. Repeat DSA testing on POD 80 demonstrated a 50% reduction in DSA, which became undetectable at POD 255. DISCUSSION: Antibody-mediated rejection (AMR) is difficult to diagnose and treat in lung transplantation. Since primary treatment options such as plasmapheresis and IVIG alone may not adequately eradicate DSA, the proteasome inhibitor bortezomib can be of additional value for the treatment of AMR. Bortezomib causes apoptosis of plasma cells, thus eliminating the production of allograft-specific DSA. CONCLUSIONS: This is the first report describing the utility of bortezomib for early graft dysfunction in a highly sensitized lung transplant recipient. Although this patient had preformed donor-specific anti-HLA antibodies, AMR was successfully treated with a combination of plasmapheresis, IVIG, and bortezomib. At time of writing, the patient continued to have excellent graft function 2 years posttransplant. Bortezomib is a potent inhibitor of plasma cell production and it appears to be useful for the treatment of antibody-mediated graft dysfunction.

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.

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.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part III: Pharmacology, medical and surgical management of post-transplant extrapulmonary conditions statements.

Patients with connective tissues disease (CTD) are often on immunomodulatory agents before lung transplantation (LTx). Till now, there's no consensus on the safety of using these agents perioperative and post-transplant. The International Society for Heart and Lung Transplantation-supported consensus document on LTx in patients with CTD addresses the risk and contraindications of perioperative and post-transplant management of the biologic disease-modifying antirheumatic drugs (bDMARD), kinase inhibitor DMARD, and biologic agents used for LTx candidates with underlying CTD, and the recommendations and management of non-gastrointestinal extrapulmonary manifestations, and esophageal disorders by medical and surgical approaches for CTD transplant recipients.

Lung Transplantation for Bronchopulmonary Dysplasia in Adults: A Clinical and Pathologic Study of 3 Cases.

Bronchopulmonary dysplasia (BPD) is usually seen in premature infants who require mechanical ventilation and oxygen therapy for acute respiratory distress. Although most patients wean from oxygen therapy by the ages of 2 to 3, rehospitalization for respiratory problems is common in these patients in adulthood. There have been few studies that document the long-term outcomes of BPD survivors and information about the pulmonary function and radiographic findings of adult BPD are limited. Data on pathologic features of adult BPD are scarce. Three adult patients who underwent recent lung transplantation for BPD from 2 institutions were identified. Clinical data including clinical presentation, chest radiographic images, pulmonary function tests, cardiac catheterization, and echocardiography were retrieved from the electronic medical records. Hematoxylin and eosin and selective elastic stained sections of the explant lungs were examined. CD31 immunohistochemical stain is performed on representative sections. All 3 cases had similar clinical and radiologic features including the history of prematurity and long-term mechanical ventilation after birth, hyperexpanded lungs with air trapping and mosaic attenuation on chest computed tomographic scan, severe obstructive changes on pulmonary function test, and pulmonary hypertension. Pathologic examination showed common features including enlarged and simplified alveoli, peribronchial, subpleural, and interlobular septal fibrosis, narrowing/obliteration of the small airways by elastosis and muscular hypertrophy, thickening of venous walls by fibromuscular hyperplasia, and bronchitis/bronchiolitis. Cholesterol granulomas were seen in 2 cases. The common pathologic findings in the lungs explain the clinical and radiologic findings. Future studies are warranted to further characterize the clinical and pathologic features of adult BPD to develop optimal management strategies for these patients.

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.

Lessons from the national emphysema treatment trial.

Medicare coverage for lung volume reduction surgery has been approved recently by the Centers for Medicare and Medicaid Services for the treatment of severe emphysema. The scientific basis for this approval stems largely from findings of the National Emphysema Treatment Trial (NETT). The purpose of this article is to review the contributions of the NETT to the management of chronic obstructive pulmonary disease.

Histopathology of Explanted Lungs From Patients With a Diagnosis of Pulmonary Sarcoidosis.

BACKGROUND: Pathologic features of end-stage pulmonary sarcoidosis (ESPS) are not well defined; anecdotal reports have suggested that ESPS may mimic usual interstitial pneumonia (UIP). We hypothesized that ESPS has distinct histologic features. METHODS: Twelve patients who received a diagnosis of pulmonary sarcoidosis and underwent lung transplantation were included. Control subjects were 10 age- and sex-matched lung transplant patients with UIP. Hematoxylin and eosin-stained tissue sections were examined for the following features: extent/pattern of fibrosis; presence and quantity (per 10 high-power fields) of fibroblast foci and granulomas; distribution and morphology of granulomas; and presence and extent of honeycomb change. Extent of fibrosis and honeycomb change in lung parenchyma was scored as follows: 1 = 1% to 25%; 2 = 26% to 50%; 3 = 51% to 75%; 4 = 76% to 100% of lung parenchyma. RESULTS: Eight of 12 cases demonstrated histologic findings typical of ESPS. All showed well-formed granulomas with associated fibrosis distributed in a distinct lymphangitic fashion. Granulomas were present in hilar or mediastinal lymph nodes from six of six patients with ESPS and none of eight control subjects. The extent of fibrosis, honeycomb change, and fibroblast foci was significantly lower in ESPS cases compared with control cases. Two patients with remote histories of sarcoidosis showed histologic features of diseases other than ESPS (UIP and emphysema) without granulomas. Two patients with atypical clinical findings demonstrated nonnecrotizing granulomas combined with either severe chronic venous hypertension or UIP. CONCLUSIONS: ESPS and UIP have distinct histopathologic features in the lungs. Patients with a pretransplant diagnosis of sarcoidosis may develop other lung diseases that account for their end-stage fibrosis.

Preoperative pulmonary artery pressure and mortality after lung transplantation.

BACKGROUND: The purpose of this study was to determine the influence of changes in pulmonary artery pressure during the waiting period on survival after lung transplantation for pulmonary fibrosis. METHODS: We identified 65 patients with pulmonary fibrosis who underwent lung transplantation from 2003 to 2010. Pulmonary artery pressure determined at listing was compared with intraoperative pressure. The primary outcome was overall survival. Co-variates included type of transplantation (single or bilateral), ischemic time, recipient and donor age and sex. RESULTS: The median age of the 65 patients undergoing transplantation was 58 years, and 27 (43%) underwent bilateral sequential transplantation. Twenty-two (35%) patients presented at transplantation with a mean pulmonary artery pressure increased by at least 10% compared to the initial pressure at the time of listing. Rising pulmonary artery pressure at transplantation was associated with increased mortality (p = 0.022). Other factors including type of operation, ischemic time, age, and sex, were not significantly associated with mortality. Post-transplantation survival was worse among recipients who had pulmonary artery pressure increased by at least 10% at transplantation (p = 0.003, logrank). CONCLUSIONS: Increasing pulmonary artery pressure while awaiting lung transplantation is associated with worse long-term survival following transplantation, and is a sign of progressively worsening disease for which greater urgency of donor organ allocation should be considered.

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.

CT venous phase venography with 64-detector CT angiography in the diagnosis of acute pulmonary embolism.

The value of computed tomographic (CT) venography in combination with CT pulmonary angiography has been questioned because of the potential dangers of radiation. Accordingly, we retrospectively evaluated the diagnostic yield of 64-detector CT angiography with CT venography. Among patients who routinely underwent CT venography with CT angiography, the CT angiogram showed acute pulmonary embolism (PE) in 206 of 1903 patients (10.8%). A positive CT venogram in a patient with a negative CT angiogram was shown in 25 of 1903 patients (1.3%). Either the CT angiogram or the CT venogram showed venous thromboembolism in 231 of 1903 patients (12.1%). The proportion of patients with venous thromboembolism diagnosed only by a CT venogram was 25 of 231 (10.8%). In conclusion, the proportion of patients with venous thromboembolism diagnosed only by a CT venogram is sufficiently high to merit consideration of its use especially in those at high risk for DVT.

Nonmedical therapy for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a category of diseases with chronic airflow obstruction and hyperinflation. The GOLD committee and the American Thoracic Society/European Respiratory Society have published detailed, evidence-based reviews of management, providing stepped-care algorithms for pharmacologic and nonpharmacologic therapy. Over the past several decades, this has led to numerous nonpharmacologic approaches to ameliorate symptoms in these patients.