This chapter will review the indications, special considerations, donor selection, surgical complications, postoperative management, and long-term outcomes in those undergoing lung transplantation for restrictive lung diseases. It will focus on unique characteristics and considerations which pertain to this specific patient population.

Rationale: Lung transplant is an effective treatment option providing survival benefit in patients with cystic fibrosis (CF). Several studies have suggested survival benefit in adults compared with pediatric patients with CF undergoing lung transplant. However, it remains unclear whether this age-related disparity persists in adult subjects with CF. Objectives: We investigated the impact of age at transplant on post-transplant outcomes in adult patients with CF. Methods: The United Network of Organ Sharing Registry was queried for all adult patients with CF who underwent lung transplantation between 1992 and 2016. Pertinent baseline characteristics, demographics, clinical parameters, and outcomes were recorded. The patients were divided into two groups based on age at transplant (18-29 yr old and 30 yr or older). The primary endpoint was survival time. Assessment of post-transplant survival was performed using Kaplan-Meier tests and log-rank tests with multivariable Cox proportional hazards analysis to adjust for confounding variables. Results: A total of 3,881 patients with CF underwent lung transplantation between 1992 and 2016; mean age was 31.0 (+/- 9.3) years. The 18-29-year-old at transplant cohort consisted of 2,002 subjects and the 30 years or older cohort had 1,879 subjects. Survival analysis demonstrated significantly higher survival in subjects in the 30 years or older cohort (9.47 yr; 95% confidence interval [CI], 8.7-10.2) compared with the 18-29-year-old cohort (5.21 yr; 95% CI, 4.6-5.8). After adjusting for confounders, survival remained higher in recipients aged 30 years or older (hazard ratio, 0.44; 95% CI, 0.2-0.9). Mortality due to allograft failure was significantly lower in patients with CF aged 30 years or older (28% vs. 36.5%; odds ratio [OR], 0.7; 95% CI, 0.6-0.8), whereas the incidence of malignancy was higher in the 30 years or older cohort (8% vs. 2.9%; OR, 3.0; 95% CI, 1.9-4.6). Conclusions: Age at transplant influences lung transplant outcomes in recipients with CF. Subjects with CF aged 30 years or older at transplant have superior survival compared with adult subjects with CF transplanted between the ages 18 and 29 years.

Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation. (C) 2021 The Author(s). Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation.

In 2009, the International Society for Heart and Lung Transplantation recognized the importance and challenges surrounding generic drug immunosuppression. As experience with generics has expanded and comfort has increased, substantial issues have arisen since that time with other aspects of immunomodulation that have not been addressed, such as access to medicines, alternative immunosuppression formulations, additional generics, implications on therapeutic drug monitoring, and implications for special populations such as pediatrics and older adults. The aim of this consensus document is to address critically each of these concerns, expand on the challenges and barriers, and provide therapeutic considerations for practitioners who manage patients who need to undergo or have undergone cardiothoracic transplantation. (C) 2020 International Society for Heart and Lung Transplantation. All rights reserved.

Background Challenges remain for establishing a specific diagnosis in cases of interstitial lung disease (ILD). Bronchoscopic lung cryobiopsy (BLC) has impacted the diagnostic impression and confidence of multidisciplinary discussions (MDDs) in the evaluation of ILD. Reports indicate that a genomic classifier (GC) can distinguish usual interstitial pneumonia (UIP) from non-UIP. Research Question What is the impact of sequentially presented data from BLC and GC on the diagnostic confidence of MDDs in diagnosing ILD? Study Design and Methods Two MDD teams met to discuss 24 patients with ILD without a definitive UIP pattern. MDD1 sequentially reviewed clinical-radiologic findings, BLC, and GC. MDD2 sequentially reviewed GC before BLC. At each step in the process the MDD diagnosis and confidence level were recorded. Results MDD1 had a significant increase in diagnostic confidence, from 43% to 93% (P = .023), in patients with probable UIP after the addition of GC to BLC. MDD2 had an increase in diagnostic confidence, from 27% to 73% (P = .074), after the addition of BLC to GC. The concordance coefficients and percentage agreement of categorical idiopathic pulmonary fibrosis (IPF) and non-IPF diagnoses were as follows: GC vs MDD1: 0.92, 96%; GC vs MDD2: 0.83, 92%; BLC1 vs MDD1: 0.67, 83%; BLC2 vs MDD2: 0.66, 83%. Interpretation GC increased diagnostic confidence when added to BLC for patients with a probable UIP pattern, and in appropriate clinical settings can be used without BLC. In contrast, BLC had the greatest impact regarding a specific diagnosis when the likelihood of UIP was considered low following clinical-radiographic review.

Donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) are associated with worse outcomes after lung transplantation. To determine the incidence and characteristics of DSA early after lung transplantation, we conducted a prospective multicenter observational study that used standardized treatment and testing protocols. Among 119 transplant recipients, 43 (36%) developed DSA: 6 (14%) developed DSA only to class I HLA, 23 (53%) developed DSA only to class II HLA, and 14 (33%) developed DSA to both class I and class II HLA. The median DSA mean fluorescence intensity (MFI) was 3197. We identified a significant association between the Lung Allocation Score and the development of DSA (HR = 1.02, 95% CI: 1.001-1.03, P = .047) and a significant association between DSA with an MFI ≥ 3000 and acute cellular rejection (ACR) grade ≥ A2 (HR = 2.11, 95% CI: 1.04-4.27, P = .039). However, we did not detect an association between DSA and survival. We conclude that DSA occur frequently early after lung transplantation, and most target class II HLA. DSA with an MFI ≥ 3000 have a significant association with ACR. Extended follow-up is necessary to determine the impact of DSA on other important outcomes.

Recent studies suggest a role of lung microbiome in pathogenesis of chronic lung allograft dysfunction. The microbiome of allograft compared to the native lung in single lung transplant recipients (SLT) has not been evaluated. This study characterizes the microbiome and metabolome signatures present in the native versus the allograft lung in single lung transplant recipients.

Rationale: Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted. Objectives: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity. Methods: Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination. Measurements and Main Results: A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow‐up was 4 years (interquartile range = 2.4‐5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48‐72 hours; P < 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination. Conclusions: The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.

The selection of appropriate recipients for lung transplantation is an evolving discipline. As experience with the procedure has developed over the last decades, the identification of transplant candidates has also changed as transplant centers strive to safely provide the therapy to as many patients possible. The International Society for Heart and Lung Transplantation (ISHLT) has developed three editions of recipient selection guidelines. Published in 1998, 2006, and 2015, these guidelines represented the best information relevant to the appropriate selection of lung transplant candidates. A discussion of areas supported by the most robust scientific data will be undertaken, but in many aspects of recipient selection, there is a paucity of data upon which to rely. Therefore, it is ultimately the prerogative and responsibility of individual centers to determine, after carefully weighing the best evidence available, whether a patient is deemed a suitable candidate at a specific program. All possible indications and contraindications for transplantation will be reviewed with attention also given to the appropriate timing of referral and listing of patients with advanced lung disease to a transplant center.

In 2016, more than 2300 lung transplants were performed in the United States, and approximately 2700 candidates were added to the wait-list.1 Clinical outcomes after lung transplantation lag behind those achieved with transplantation of other solid organs, with average 5-year survival of 55%.1 Despite this, lung transplantation is a relatively understudied area of clinical research, and few prospective randomized trials are conducted in lung transplantation. In June 2017, the National Heart, Lung, and Blood Institute (NHLBI) and American Association for Thoracic Surgery (AATS) co-sponsored a workshop designed to bring participants together to summarize the current state of the science in adult lung transplantation, identify knowledge gaps, and determine priorities in clinical lung transplant research that could be addressed in the near future.

Primary graft dysfunction (PGD) refers to the syndrome of acute lung injury early after lung transplantation (LTx).1 In 2005, based on the need for a reliable and valid definition with clear taxonomy, the first International Society for Heart and Lung Transplantation (ISHLT) Working Group on PGD proposed a consensus-based standardized definition and grading system.1 This definition has since been used to characterize PGD clinically by diffuse alveolar infiltrates on chest X-ray imaging, with the degree of associated hypoxemia determining its severity (Table 1).

Cell-free DNA (cfDNA) from lung transplant recipients was analyzed using a clinical-grade targeted next-generation sequencing (NGS) method to determine the correlation between donor-derived cell-free DNA (dd-cfDNA) and transbronchial histopathology grades. These results were compared to published results using a shotgun sequencing method with prior donor and recipient genotyping to determine the correlation between methods.

Consideration of prophylactic mastectomy surgery following transplantation requires complex medical decision-making, and bias against elective surgery exists because of concern for post-operative complications. Prevention of cancer in transplant recipients is of utmost importance, given the risks of treating malignancy in an immunosuppressed patient. We present a patient case and review of the literature to support a thorough pre-transplantation evaluation of family history and consideration of prophylactic interventions to safeguard the quality of life of transplant recipients. J. Surg. Oncol. 2016;113:605-608. © 2016 Wiley Periodicals, Inc.

While multiple donor characteristics have been cited as ideal for lung transplantation, there are minimal widely accepted exclusion criteria. One criterion that many centers view with hesitation is death by drowning. However, recent literature suggests such donors may result in acceptable outcomes following transplantation. This review highlights a case of a patient who underwent a successful bilateral lung transplant from a donor following a drowning event. A review of the current literature is presented, concluding with a new proposed set of favorable donor criteria following death by drowning.

Although controlled donation after circulatory determination of death (cDCDD) could increase the supply of donor lungs within the United States, the yield of lungs from cDCDD donors remains low compared with donation after neurologic determination of death (DNDD). To explore the reason for low lung yield from cDCDD donors, Scientific Registry of Transplant Recipient data were used to assess the impact of donor lung quality on cDCDD lung utilization by fitting a logistic regression model. The relationship between center volume and cDCDD use was assessed, and the distance between center and donor hospital was calculated by cDCDD status. Recipient survival was compared using a multivariable Cox regression model. Lung utilization was 2.1% for cDCDD donors and 21.4% for DNDD donors. Being a cDCDD donor decreased lung donation (adjusted odds ratio 0.101, 95% confidence interval [CI] 0.085–0.120). A minority of centers have performed cDCDD transplant, with higher volume centers generally performing more cDCDD transplants. There was no difference in center-to-donor distance or recipient survival (adjusted hazard ratio 1.03, 95% CI 0.78–1.37) between cDCDD and DNDD transplants. cDCDD lungs are underutilized compared with DNDD lungs after adjusting for lung quality. Increasing transplant center expertise and commitment to cDCDD lung procurement is needed to improve utilization.

RATIONALEAlthough lung transplant recipient survival is better at higher volume centers, the effect of center volume on admission cost and early hospital readmission is unknown.OBJECTIVESTo understand the association between transplant center volume and recipient risk-adjusted transplant admission cost, in-hospital mortality, and early hospital readmission in lung transplant recipients.METHODSMedicare lung transplant recipients from May 4, 2005 to December 31, 2011 were identified through linkage of transplant registry and Medicare administrative claims. Transplant admission cost was extracted, adjusted for regional price variation, and compared across low-, intermediate-, and high-volume centers. A multivariable hierarchical generalized linear regression model was used to assess the effect of transplant center volume on recipient adjusted cost. Modified Poisson regression models were used to assess adjusted in-hospital mortality and early hospital readmission by transplant center volume.MEASUREMENTS AND MAIN RESULTSThere were 3,128 Medicare lung transplant recipients identified. Unadjusted transplant cost was lower at high-volume centers (mean, $131,352 [SD, ±$106,165]; median, $90,177; interquartile range [IQR], $79,165-$137,915) than at intermediate-volume (mean, $138,792 [SD, ±$106,270]; median, $93,024; IQR, $82,700-$154,857) or low-volume (mean, $143,609 [SD, ±$123,316]; median, $95,234; IQR, $83,052-$152,149) centers (P < 0.0001). After adjusting for recipient health risk, low-volume centers had an 11.66% greater transplant admission cost (P = 0.040), a 41% greater risk for in-hospital mortality (P = 0.015), and a 14% greater risk for early hospital readmission (P = 0.033) compared with high-volume centers. There was no significant difference in transplant cost, in-hospital mortality, or early hospital readmission between intermediate- and high-volume centers.CONCLUSIONSLung transplant admission cost, in-hospital mortality, and early hospital readmission rate are lower at high-volume centers compared with low-volume centers.

RATIONALE: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. OBJECTIVES:To determine changes in resource use over time in lung transplant admissions. METHODS: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. MEASUREMENTS AND MAIN RESULTS: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). CONCLUSIONS:LAS implementation is associated with a significant increase in resource use during index hospitalization for lung transplant.