The SHELTER Trial of Transplanting Hepatitis C Virus-Infected Lungs Into Uninfected Recipients.

SHELTER is a trial of transplanting lungs from deceased donors with hepatitis C virus (HCV) infection into HCV-negative candidates (sponsor: Merck; NCT03724149). Few trials have reported outcomes using thoracic organs from HCV-RNA+ donors and none have reported quality of life (QOL). Methods: This study is a single-arm trial of 10 lung transplants at a single center. Patients were included who were between 18 and 67 y of age and waitlisted for lung-only transplant. Patients were excluded who had evidence of liver disease. Primary outcome was HCV cure (sustained virologic response 12 wk after completing antiviral therapy). Recipients longitudinally reported QOL using the validated RAND-36 instrument. We also applied advanced methods to match HCV-RNA+ lung recipients to HCV-negative lung recipients in a 1:3 ratio at the same center. Results: Between November 2018 and November 2020, 18 patients were consented and opted-in for HCV-RNA+ lung offers in the allocation system. After a median of 37 d (interquartile range [IQR], 6-373) from opt-in, 10 participants received double lung transplants. The median recipient age was 57 y (IQR, 44-67), and 7 recipients (70%) had chronic obstructive pulmonary disease. The median lung allocation score at transplant was 34.3 (IQR, 32.7-86.9). Posttransplant, 5 recipients developed primary graft dysfunction grade 3 on day 2 or 3, although none required extracorporeal membrane oxygenation. Nine patients received elbasvir/grazoprevir, whereas 1 patient received sofosbuvir/velpatasvir. All 10 patients were cured of HCV and survived to 1 y (versus 83% 1-y survival among matched comparators). No serious adverse events were found to be related to HCV or treatment. RAND-36 scores showed substantial improvement in physical QOL and some improvement in mental QOL. We also examined forced expiratory volume in 1 s-the most important lung function parameter after transplantation. We detected no clinically important differences in forced expiratory volume in 1 s between the HCV-RNA+ lung recipients versus matched comparators. Conclusions: SHELTER adds important evidence regarding the safety of transplanting HCV-RNA+ lungs into uninfected recipients and suggests QOL benefits.

Cryoablation in lung transplantation: Its impact on pain, opioid use, and outcomes.

Objective: To assess the effect of intraoperative cryoablation on postoperative patient-reported pain, opioid use, and clinical outcomes in lung transplantation. Methods: We performed a single-center retrospective cohort study of adult lung transplant recipients from August 2017 to September 2018. We compared outcomes of patients who received intraoperative cryoablation of the intercostal nerves with those who did not. Primary outcomes were postoperative patient-reported pain scores and opioid use. Secondary outcomes included postoperative sedation and agitation levels and perioperative outcomes. Data were abstracted from patients' electronic health records. Results: Of the 102 patients transplanted, 45 received intraoperative cryoablation (intervention group) and 57 received the standard of care, which did not include intercostal or serratus blocks or immediate postoperative epidural placement (control group). The intervention group had significantly lower median and maximum postoperative pain scores at days 3 and 7 and significantly lower oral opioid use at days 3, 7, and 14 compared with the control group. Chronic opioid use at 3 and 6 months' posttransplant was lower in the intervention group. Differences in perioperative outcomes, including length of mechanical ventilation, sedation and agitation levels, and hospital stay, were not clinically meaningful. Survival at 30 days and 1 year was superior in the intervention compared with the control group. Conclusions: Findings suggest that use of intraoperative cryoablation is an effective approach for treating pain and reducing opioid use in patients who undergo lung transplant, but a randomized study across multiple institutions is needed to confirm these findings.

Decision-making Among Hepatitis C Virus-negative Transplant Candidates Offered Organs from Donors with HCV Infection.

Background: Historically, many organs from deceased donors with hepatitis C virus (HCV) were discarded. The advent of highly curative direct-acting antiviral (DAA) therapies motivated transplant centers to conduct trials of transplanting HCV-viremic organs (nucleic acid amplification test positive) into HCV-negative recipients, followed by DAA treatment. However, the factors that influence candidates' decisions regarding acceptance of transplant with HCV-viremic organs are not well understood. Methods: To explore patient-level perceptions, influences, and experiences that inform candidate decision-making regarding transplant with organs from HCV-viremic donors, we conducted a qualitative semistructured interview study embedded within 3 clinical trials investigating the safety and efficacy of transplanting lungs and kidneys from HCV-viremic donors into HCV-negative recipients. The study was conducted from June 2019 to March 2021. Results: Among 44 HCV-negative patients listed for organ transplant who were approached for enrollment in the applicable clinical trial, 3 approaches to decision-making emerged: positivist, risk analyses, and instinctual response. Perceptions of risk contributed to conceptualizations of factors influencing decisions. Moreover, most participants relied on multiple decision-making approaches, either simultaneously or sequentially. Conclusions: Understanding how different decisional models influence patients' choices regarding transplant with organs from HCV-viremic donors may promote shared decision-making among transplant patients and providers.

Causes, Preventability, and Cost of Unplanned Rehospitalizations Within 30 Days of Discharge After Lung Transplantation.

BACKGROUND: Unplanned rehospitalizations (UR) within 30 days of discharge are common after lung transplantation. It is unknown whether UR represents preventable gaps in care or necessary interventions for complex patients. The objective of this study was to assess the incidence, causes, risk factors, and preventability of UR after initial discharge after lung transplantation. METHODS: This was a single-center prospective cohort study. Subjects completed a modified short physical performance battery to assess frailty at listing and at initial hospital discharge after transplantation and the State-Trait Anxiety Inventory at discharge. For each UR, a study staff member and the patient's admitting or attending clinician used an ordinal scale (0, not; 1, possibly; 2, definitely preventable) to rate readmission preventability. A total sum score of 2 or higher defined a preventable UR. RESULTS: Of the 90 enrolled patients, 30 (33.3%) had an UR. The single most common reasons were infection (7 [23.3%]) and atrial tachyarrhythmia (5 [16.7%]). Among the 30 URs, 9 (30.0%) were deemed preventable. Unplanned rehospitalization that happened before day 30 were more likely to be considered preventable than those between days 30 and 90 (30.0% versus 6.2%, P = 0.04). Discharge frailty, defined as short physical performance battery less than 6, was the only variable associated with UR on multivariable analysis (odds ratio, 3.4; 95% confidence interval, 1.1-11.8; P = 0.04). CONCLUSIONS: Although clinicians do not rate the majority of UR after lung transplant as preventable, discharge frailty is associated with UR. Further research should identify whether modification of discharge frailty can reduce UR.

Massive donor transfusion potentially increases recipient mortality after lung transplantation.

OBJECTIVE: Donor blood transfusion has been identified as a potential risk factor for primary graft dysfunction and by extension early mortality. We sought to define the contributing risk of donor transfusion on early mortality for lung transplant. METHODS: Donor and recipient data were abstracted from the Organ Procurement and Transplantation Network database updated through June 30, 2014, which included 86,398 potential donors and 16,255 transplants. Using the United Network for Organ Sharing 4-level designation of transfusion (no blood, 1-5 units, 6-10 units, and >10 units, massive), we analyzed all-cause mortality at 30-days with the use of logistic regression adjusted for confounders (ischemic time, donor age, recipient diagnosis, lung allocation score and recipient age, and recipient body mass index). Secondary analyses assessed 90-day and 1-year mortality and hospital length of stay. RESULTS: Of the 16,255 recipients transplanted, 8835 (54.35%) donors received at least one transfusion. Among those transfused, 1016 (6.25%) received a massive transfusion, defined as >10 units. Those donors with massive transfusion were most commonly young trauma patients. After adjustment for confounding variables, donor massive transfusion was associated significantly with an increased risk in 30-day (P = .03) and 90-day recipient mortality (P = .01) but not 1-year mortality (P = .09). There was no significant difference in recipient length of stay or hospital-free days with respect to donor transfusion. CONCLUSIONS: Massive donor blood transfusion (>10 units) was associated with early recipient mortality after lung transplantation. Conversely, submassive donor transfusion was not associated with increased recipient mortality. The mechanism of increased early mortality in recipients of lungs from massively transfused donors is unclear and needs further study but is consistent with excess mortality seen with primary graft dysfunction in the first 90 days posttransplant.

Adipose Gene Expression Profile Changes With Lung Allograft Reperfusion.

Obesity is a risk factor for primary graft dysfunction (PGD), a form of lung injury resulting from ischemia-reperfusion after lung transplantation, but the impact of ischemia-reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from six subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were downregulated in the postreperfusion time compared with baseline. Long pentraxin-3, a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5-fold increase, p = 0.04). Fibronectin leucine-rich transmembrane protein-3, a gene associated with cell adhesion and receptor signaling, was the most downregulated gene (4.3-fold decrease, p = 0.04). Ischemia-reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of nonobese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant.

The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia.

BACKGROUND: Donor smoking history and higher fraction of inspired oxygen (FIO2) at reperfusion are associated with primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidative injury biomarkers would be elevated in PGD, with higher levels associated with donor exposure to cigarette smoke and recipient hyperoxia at reperfusion. METHODS: We performed a nested case-control study of 72 lung transplant recipients from the Lung Transplant Outcomes Group cohort. Using mass spectroscopy, F2-isoprostanes and isofurans were measured in plasma collected after transplantation. Cases were defined in 2 ways: grade 3 PGD present at day 2 or day 3 after reperfusion (severe PGD) or any grade 3 PGD (any PGD). RESULTS: There were 31 severe PGD cases with 41 controls and 35 any PGD cases with 37 controls. Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (28.6 pg/ml vs 19.8 pg/ml, p = 0.03). Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (29.6 pg/ml vs 19.0 pg/ml, p = 0.03) among patients reperfused with FIO2 >40%. Among recipients of lungs from donors with smoke exposure, plasma F2-isoprostane (38.2 pg/ml vs 22.5 pg/ml, p = 0.046) and isofuran (66.9 pg/ml vs 34.6 pg/ml, p = 0.046) levels were higher in severe PGD compared with control subjects. CONCLUSIONS: Plasma levels of lipid peroxidation products are higher in patients with severe PGD, in recipients of lungs from donors with smoke exposure, and in recipients exposed to higher Fio2 at reperfusion. Oxidative injury is an important mechanism of PGD and may be magnified by donor exposure to cigarette smoke and hyperoxia at reperfusion.