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Alpha-1 antitrypsin (AAT) augmentation is effective in slowing the progression of emphysema due to AAT deficiency (AATD) but cannot prevent eventual progression to end-stage lung disease and complete respiratory failure, which is the leading cause of death for individuals with severe AATD. When patients develop end-stage lung disease, lung transplantation is the only treatment option available, and this can improve lung physiology and patient health status. The available data suggest that survival rates for lung transplantation are significantly higher for patients with AATD-related chronic obstructive pulmonary disease (COPD) compared with non-AATD-related COPD, but, conversely, there is a higher risk of common post-lung transplant complications in patients with AATD versus non-AATD COPD. Nevertheless, lung transplantation (single and bilateral) is favorable for patients with AATD. After respiratory failure, the second leading cause of death in patients with AATD is liver disease, for example, cirrhosis and hepatocellular carcinoma, caused by the accumulation of mutant forms of AAT retained within the liver. As with lung disease, the only treatment option for end-stage liver disease is liver transplantation. Survival rates for patients with AATD undergoing liver transplantation are also favorable, and patients, particularly pediatric patients, have benefitted from advancements in peri-/post-surgical care. As the majority of AAT is produced by the liver, the AAT phenotype of the recipient becomes that of the donor, meaning that AAT serum levels should be normalized (if the donor is AAT-replete), halting further lung and liver disease progression. However, post-liver transplant respiratory function may continue to decline in line with normal age-related lung function decline. In the most severe cases, where patients have simultaneous end-stage lung and liver disease, combined lung and liver transplantation is a treatment option with favorable outcomes. However, there is very little information available on this procedure in patients with AATD.

Abstract Rationale 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. Objectives 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. Methods 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. Measurements and Main Results 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. Conclusions 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.

Abstract Rationale Lower respiratory tract infections due to respiratory syncytial virus (RSV) are associated with development of bronchiolitis obliterans syndrome in lung transplant (LTX) recipients. ALN-RSV01 is a small interfering RNA targeting RSV replication. Objectives To determine the safety and explore the efficacy of ALN-RSV01 in RSV infection. Methods We performed a randomized, double-blind, placebo-controlled trial in LTX recipients with RSV respiratory tract infection. Patients were permitted to receive standard of care for RSV. Aerosolized ALN-RSV01 (0.6 mg/kg) or placebo was administered daily for 3 days. Viral load was determined by quantitative reverse transcriptase–polymerase chain reaction on serial nasal swabs. Patients completed symptom score cards twice daily. Lung function, including the incidence of new-onset or progressive bronchiolitis obliterans syndrome, was recorded at Day 90. Measurements and Main Results We enrolled 24 patients (ALN-RSV01, n = 16; placebo, n = 8); randomization was stratified by ribavirin use. ALN-RSV01 was well tolerated, with no drug-related serious adverse events or post-inhalation perturbations in lung function. Interpretation of viral measures was confounded by baseline differences between the two groups in viral load and time from symptom onset to first dose. Mean daily symptom scores were lower in subjects receiving ALN-RSV01, and the mean cumulative daily total symptom score was significantly lower with ALN-RSV01 (114.7 ± 63.13 vs. 189.3 ± 99.59, P = 0.035). At Day 90, incidence of new or progressive bronchiolitis obliterans syndrome was significantly reduced in ALN-RSV01 recipients compared with placebo (6.3% vs. 50%, P = 0.027). Conclusions ALN-RSV01 was safe and may have beneficial effects on long-term allograft function in LTX patients infected with RSV. Clinical trial registered with www.clinicaltrials.gov (NCT00658086).

Emphysema occurs in a subgroup of patients with chronic obstructive pulmonary disease and patients with the genetic defect of alpha1-antitrypsin deficiency who have a smoking history of many years' duration. Emphysema is generally the result of a chronic and progressive destruction of the alveolar structures, which is believed to be driven by chronic inflammation, infections, oxidative stress, and an imbalance of protease and antiprotease activity. Here, we use microarray technology to characterize the gene expression profile of lung tissue samples obtained from patients with advanced emphysema and that obtained from healthy subjects. We hypothesized that the gene expression profile of emphysema lung tissue is distinct when compared with the expression profile of normal lungs. We report that severely emphysematous tissue is characterized by a global decrease in gene expression and by an increased abundance of transcripts encoding proteins involved in inflammation, immune responses, and proteolysis. Whereas the gene expression profile is to some degree shared between “usual” emphysema and alpha1-antitrypsin deficiency–related emphysema, there are statistically significant differences in the modulation of groups of genes associated with protein and energy metabolism, and immune function, which allow distinction between these two emphysema types on the lung tissue level.

In 2005, the lung allocation score (LAS) was implemented to prioritize organ allocation to minimize waiting-list mortality and maximize 1-year survival. It resulted in transplantation of older and sicker patients without changing 1-year survival. Its effect on resource use is unknown. To determine changes in resource use over time in lung transplant admissions. Solid organ transplant recipients were identified within the Nationwide Inpatient Sample (NIS) data from 2000 to 2011. Joinpoint regression methodology was performed to identify a time point of change in mean total hospital charges among lung transplant and other solid-organ transplant recipients. Two temporal lung transplant recipient cohorts identified by joinpoint regression were compared for baseline characteristics and resource use, including total charges for index hospitalization, charges per day, length of stay, discharge disposition, tracheostomy, and need for extracorporeal membrane oxygenation. A significant point of increased total hospital charges occurred for lung transplant recipients in 2005, corresponding to LAS implementation, which was not seen in other solid-organ transplant recipients. Total transplant hospital charges increased by 40% in the post-LAS cohort ($569,942 [$53,229] vs. $407,489 [$28,360]) along with an increased median length of stay, daily charges, and discharge disposition other than to home. Post-LAS recipients also had higher post-transplant use of extracorporeal membrane oxygenation (odds ratio, 2.35; 95% confidence interval, 1.56-3.55) and higher incidence of tracheostomy (odds ratio, 1.52; 95% confidence interval, 1.22-1.89). LAS implementation is associated with a significant increase in resource use during index hospitalization for lung transplant.

Abstract Rationale Between 10% and 57% of lung transplant (LTx) recipients develop primary graft dysfunction (PGD) within 72 hours of LTx. PGD is clinically and histologically analogous to the acute respiratory distress syndrome. In patients at risk for or with acute respiratory distress syndrome, lung-protective ventilation strategies (low tidal volume and positive end-expiratory pressure) improve outcomes. There is, however, little information available on mechanical ventilation strategies after LTx. Objectives Our aim in this international survey was to describe the current practices of mechanical ventilation immediately after LTx. Methods An electronic survey was sent to the medical and surgical directors of U.S. LTx programs (n = 111) and to members of the Pulmonary Council of the International Society for Heart and Lung Transplantation (n = 470). Results A total of 149 individuals from 18 countries responded to the questionnaire. The most common modes of ventilation were pressure assist/control (37%) and volume assist/control (35%). Tidal volumes were most often determined by recipient characteristics. Donor characteristics were rarely considered (35%) and were infrequently known by the team managing the ventilator (42%). When presented with a choice of ideal tidal volumes, a majority of respondents selected 6 ml/kg recipient predicted body weight (58%), fewer selected 10 ml/kg (21%), and none selected 15 ml/kg. A majority preferred limiting the fraction of inspired oxygen rather than positive end-expiratory pressure (PEEP) (69% versus 31%, P = 0.006). The median minimum PEEP was 5 cm H2O, and the median maximum PEEP was 11.5 cm H2O. The presence of PGD increased the perceived importance of monitoring plateau pressure to adjust tidal volumes. The median plateau pressure limit perceived as a threshold triggering reduction in tidal volume was 30 cm H2O. Conclusions Most respondents reported using lung-protective approaches to mechanical ventilation after lung transplantation. Low tidal volumes based on recipient characteristics were frequently chosen. Donor characteristics often were not considered and frequently were not known by the team managing mechanical ventilation after LTx.

Small airway fibrosis (bronchiolitis obliterans syndrome) is the primary obstacle to long-term survival following lung transplantation. Here, we show the importance of functional microvasculature in the prevention of epithelial loss and fibrosis due to rejection and for the first time, relate allograft microvascular injury and loss of tissue perfusion to immunotherapy-resistant rejection. To explore the role of alloimmune rejection and airway ischemia in the development of fibroproliferation, we used a murine orthotopic tracheal transplant model. We determined that transplants were reperfused by connection of recipient vessels to donor vessels at the surgical anastomosis site. Microcirculation through the newly formed vascular anastomoses appeared partially dependent on VEGFR2 and CXCR2 pathways. In the absence of immunosuppression, the microvasculature in rejecting allografts exhibited vascular complement deposition, diminished endothelial CD31 expression, and absent perfusion prior to the onset of fibroproliferation. Rejecting grafts with extensive endothelial cell injury were refractory to immunotherapy. After early microvascular loss, neovascularization was eventually observed in the membranous trachea, indicating a reestablishment of graft perfusion in established fibrosis. One implication of this study is that bronchial artery revascularization at the time of lung transplantation may decrease the risk of subsequent airway fibrosis.

Lung ischemia-reperfusion (IR) injury contributes to post-transplant complications, including primary graft dysfunction. Decades of reports show that reactive oxygen species generated during lung IR contribute to pulmonary vascular endothelial barrier disruption and edema formation, but the specific target molecule(s) that “sense” injury-inducing oxidant stress to activate signaling pathways culminating in pathophysiologic changes have not been established. This review discusses evidence that mitochondrial DNA (mtDNA) may serve as a molecular sentinel wherein oxidative mtDNA damage functions as an upstream trigger for lung IR injury. First, the mitochondrial genome is considerably more sensitive than nuclear DNA to oxidant stress. Multiple studies suggest that oxidative mtDNA damage could be transduced to physiologic dysfunction by pathways that are either a direct consequence of mtDNA damage per se or involve formation of proinflammatory mtDNA damage-associated molecular patterns. Second, transgenic animals or cells overexpressing components of the base excision DNA repair pathway in mitochondria are resistant to oxidant stress–mediated pathophysiologic effects. Finally, published and preliminary studies show that pharmacologic enhancement of mtDNA repair or mtDNA damage–associated molecular pattern degradation suppresses reactive oxygen species–induced or IR injury in multiple organs, including preclinical models of lung procurement for transplant. Collectively, these findings point to the interesting prospect that pharmacologic enhancement of DNA repair during procurement or ex vivo lung perfusion may increase the availability of lungs for transplant and reduce the IR injury contributing to primary graft dysfunction.

To demonstrate that pulmonary capillaritis and diffuse alveolar hemorrhage (DAH) occur and are isolated to the lung and therefore not part of systemic vasculitis at the time of the DAH episode in rheumatoid arthritis (RA) and mixed connective tissue disease (MCTD). Lung biopsy specimens from patients with DAH were reviewed and those with the histologic features of pulmonary capillaritis were identified. The patients were selected from seven Denver-area general hospitals. Fifty-eight patients with biopsy specimen proved pulmonary capillaritis (1991 to 1997) were identified and classified according to disease. Three patients met the American Rheumatism Association criteria for RA and one patient fulfilled clinical and serologic criteria for MCTD. All clinical, laboratory, and radiographic data on initial presentation and at follow-up periods were extracted from the charts of the four study patients. Histologic slides were reviewed and immunofluorescent studies of lung tissue were performed. All four patients had a connective tissue disease diagnosis prior to the DAH episode. Symptoms referable to pulmonary capillaritis were of short duration (2 to 14 days) and there was no clinical or serologic evidence for an accompanying systemic vasculitis, in particular glomeronephritis. Three patients, two with RA and one with MCTD, demonstrated pulmonary immune complex deposition. Three resolved their illness following IV methylprednisilone and cyclophosphamide therapy. One RA patient died following a myocardial infarction. In the three survivors, no further episodes of DAH have occurred after a mean of 24 months (range, 10 to 48 months). To our knowledge, these are the first cases of DAH due to pulmonary capillaritis documented to complicate RA and MCTD. The capillaritis was not part of a systemic vasculitis at the time of the DAH episode, but rather represented an isolated small-vessel vasculitis of the lungs in this group of patients. Immune complex deposition may be involved in the pathogenesis.