Faculty Bibliography

BACKGROUND:The effect of prolonged allograft ischemic time on lung transplant outcomes remains controversial, with most studies associating it with increased mortality, but this effect is partly mitigated by center volume. This study sought to evaluate the mechanism of these findings and clarify the impact of ischemic time on short-term outcomes in a national sample. METHODS:Data on lung transplants (January 2010-Janary 2017) were extracted from the Scientific Registry of Transplant Recipients database. Ischemic time was dichotomized as prolonged ischemic time (PIT) or no PIT (N-PIT) at 6 hours. High-volume centers were defined as the top quintile. The primary outcome was 30-day, 1-year, and 3-year mortality; secondary outcomes included in-hospital complications and 72-hour oxygenation. RESULTS:Among 11,809 records, there were significant differences between PIT and N-PIT recipients by demographics, lung allocation score, and donor organ metrics. In a 1:1 propensity score-matched cohort (n = 6422), PIT recipients had reduced survival compared with N-PIT at 3 years (66.5% vs 68.8%, P = .031). On multivariable analysis, this effect persisted among low-volume but not high-volume centers. PIT recipients were more likely to require reintubation, prolonged (>5 days) mechanical ventilation, hemodialysis, longer stay, and acute rejection (all P < .01). Except for reintubation, these disparities were present at both high- and low-volume centers independently. Ischemic time had no effect on 72-hour oxygenation. CONCLUSIONS:PIT remains associated with higher rates of postoperative complications and reduced short-term survival. While center volume ameliorated the survival impact, this was not achieved by reducing postoperative complications. Further research is warranted before broadening ischemic time thresholds among low-volume centers.

Rates of lung donation have increased over the past several years. This has been accomplished through the utilization of donors with extended criteria, the creation of donor hospitals or centers, and the optimization of lungs through the implementation of donor management protocols. These measures have resulted in augmenting the pool of available donors thereby decreasing the wait time for lung transplantation candidates. Although transplant programs vary significantly in their acceptance rates of these organs, studies have not shown any difference in the incidence of primary graft dysfunction or overall mortality for the recipient when higher match-run sequence organs are accepted. Yet, the level of comfort in accepting these donors varies among transplant programs. This deviation in practice results in these organs going to lower-priority candidates thereby increasing the waitlist time of other recipients and ultimately has a deleterious effect on an institution's waitlist mortality.

Xenotransplantation promises to alleviate the issue of donor organ shortages and to decrease waiting times for transplantation. Recent advances in genetic engineering have allowed for the creation of pigs with up to 16 genetic modifications. Several combinations of genetic modifications have been associated with extended graft survival and life-supporting function in experimental heart and kidney xenotransplants. Lung xenotransplantation carries specific challenges related to the large surface area of the lung vascular bed, its innate immune system's intrinsic hyperreactivity to perceived 'danger', and its anatomic vulnerability to airway flooding after even localized loss of alveolocapillary barrier function. This article discusses the current status of lung xenotransplantation, and challenges related to immunology, physiology, anatomy, and infection. Tissue engineering as a feasible alternative to develop a viable lung replacement solution is discussed.

OBJECTIVE:There is a shortage of donor lungs relative to need, but overall donor organ utilization remains low. The most common reason for refusal is organ quality, but the standards applied to selection vary. In this study we sought to characterize differences in lung utilization according to quality across several clinically distinct recipient pools. METHODS:Data on donor lungs recovered (April 2006 to September 2019) were extracted from the Scientific Registry of Transplant Recipients database. Organs were classified as ideal, standard, or extended quality according to their poorest metric among selected parameters. Subanalyses were performed on the basis of procedure type, age, lung allocation score, era, and alternative definitions of extended quality. Recipient traits and survival according to organ quality were assessed. RESULTS:Of 156,022 lungs analyzed during the study period, 25,777 (16.5%) were transplanted. There was no difference in quality distribution for single and bilateral transplants. Young candidates were more likely to receive ideal (14.7% vs 12.3%) or standard (9.5% vs 8.2%) lungs, but not extended lungs (75.9% vs 79.5%; all P < .01). Absolute differences in distribution according to lung allocation score quartile were small (<2%). Extended quality donor utilization increased over time. Survival according to donor category was similar at 1 and 3 years post transplant in unadjusted and Cox regression analyses. CONCLUSIONS:Extended quality lungs comprise an increasing share of transplants in a national sample. Organ selection varies according to recipient age and lung allocation score. However, absolute differences in quality distribution are small, and adverse effects on outcomes are limited to organs with multiple extended qualifying characteristics.

Lung transplantation is the only potentially curative treatment for end-stage lung failure and successfully improves both long-term survival and quality of life. However, lung transplantation is limited by the shortage of suitable donor lungs. This discrepancy in organ supply and demand has prompted researchers to seek alternative therapies for end-stage lung failure. Tissue engineering (bioengineering) organs has become an attractive and promising avenue of research, allowing for the customized production of organs on demand, with potentially perfect biocompatibility. While breakthroughs in tissue engineering have shown feasibility in practice, they have also uncovered challenges in solid organ applications due to the need not only for structural support, but also vascular membrane integrity and gas exchange. This requires a complex engineered interaction of multiple cell types in precise anatomical locations. In this article, we discuss the process of creating bioengineered lungs and the challenges inherent therein. We summarize the relevant literature for selecting appropriate lung scaffolds, creating decellularization protocols, and using bioreactors. The development of completely artificial lung substitutes will also be reviewed. Lastly, we describe the state of current research, as well as future studies required for bioengineered lungs to become a realistic therapeutic modality for end-stage lung disease. Applications of bioengineering may allow for earlier intervention in end-stage lung disease and have the potential to not only halt organ failure, but also significantly reverse disease progression.

Little is known about the effects of hepatitis C viremia on immunologic outcomes in the era of direct-acting antivirals. We conducted a prospective, single-arm trial of lung transplantation from hepatitis C-infected donors into hepatitis C-naïve recipients (n = 21). Recipients were initiated on glecaprevir-pibrentasvir immediately post-transplant and were continued on therapy for a total of 8 weeks. A control group of recipients of hepatitis C-negative lungs were matched 1:1 on baseline variables (n = 21). The primary outcome was the frequency of acute cellular rejection over 1-year post-transplant. Treatment with glecaprevir-pibrentasvir was well tolerated and resulted in viremia clearance after a median of 16 days of therapy (IQR 10-24 days). At one year, there was no difference in incidence of acute cellular rejection (71.4% vs. 85.7%, P = .17) or rejection requiring treatment (33.3% vs. 57.1%, P = .12). Mean cumulative acute rejection scores were similar between groups (.46 [SD ± .53] vs. .52 [SD ± .37], P = .67). Receipt of HCV+ organs was not associated with acute rejection on unadjusted Cox regression analysis (HR .55, 95% CI .28-1.11, P = .09), or when adjusted for risk factors known to be associated with acute rejection (HR .57, 95% CI .27-1.21, P = .14). Utilization of hepatitis C infected lungs with immediate treatment leads to equivalent immunologic outcomes at 1 year.

OBJECTIVES/OBJECTIVE:Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may develop end-stage lung disease requiring lung transplantation. We report the clinical course, pulmonary pathology with radiographic correlation, and outcomes after lung transplantation in three patients who developed chronic respiratory failure due to postacute sequelae of SARS-CoV-2 infection. METHODS:A retrospective histologic evaluation of explanted lungs due to coronavirus disease 2019 was performed. RESULTS:None of the patients had known prior pulmonary disease. The major pathologic findings in the lung explants were proliferative and fibrotic phases of diffuse alveolar damage, interstitial capillary neoangiogenesis, and mononuclear inflammation, specifically macrophages, with varying numbers of T and B lymphocytes. The fibrosis varied from early collagen deposition to more pronounced interstitial collagen deposition; however, pulmonary remodeling with honeycomb change was not present. Other findings included peribronchiolar metaplasia, microvascular thrombosis, recanalized thrombi in muscular arteries, and pleural adhesions. No patients had either recurrence of SARS-CoV-2 infection or allograft rejection following transplant at this time. CONCLUSIONS:The major pathologic findings in the lung explants of patients with SARS-CoV-2 infection suggest ongoing fibrosis, prominent macrophage infiltration, neoangiogenesis, and microvascular thrombosis. Characterization of pathologic findings could help develop novel management strategies.

Introduction: Community-acquired Cytomegalovirus (CMV) infection in a seronegative transplant recipient (R) from a seronegative donor (D) is a rare occurrence that carries significant clinical and prognostic implications. Few case reports exist describing this entity in lung transplant recipients. Case Report: A 58-year-old man with bilateral lung transplant for sarcoidosis presented with three days of diarrhea and dyspnea. He underwent an uneventful bilateral lung transplantation (CMV D-/R-) six weeks prior, receiving basiliximab and methylprednisolone for induction. He was discharged two weeks later on tacrolimus, mycophenolate motefil, and prednisone taper as maintenance immunosuppression. He was receiving acyclovir for herpes viruses prophylaxis. He was seen weekly post-discharge and continued to have clear chest radiographs and unremarkable bloodwork. On presentation, his physical examination was notable for decreased breath sounds at the right base. His laboratory values revealed creatinine of 2.4 mg/dL. His chest radiograph showed new right pleural effusion. He was admitted for hydration and diarrhea work up. Abdominal computed tomography (CT) revealed mild diverticulitis with no colitis and his stool studies were positive for Clostridium difficile. Chest CT showed hazy and linear markings with thin-walled cysts in right lower lobe, adjacent to a moderate pleural effusion. CMV by polymerase chain reaction resulted at 318,200 copies/mL. He was treated with intravenous ganciclovir and underwent a thoracenthesis. Half a liter of clear pleural fluid was removed and was notable for lymphocytic predominance of 72% as well as polytypic plasma cells and a small number of B lymphocytes with no surface immunoglobulins on flow cytometry. Subsequent radiograph showed completely re-expanded lung. Within two days, the effusion re-accumulated and additional half a liter were drained, revealing of 95% lymphocytes, with complete re-expansion of the lung. Concomitant viral load remained elevated at 150,328 copies/mL. He was discharged on valganciclovir, his viral load decreased to an undetectable level, and his radiographs have remained free of effusion. While primary CMV infection is rare in low-risk lung transplant recipients, CMV disease should be considered in the differential diagnosis of early post-operative pleural effusion.
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