Ex vivo lung perfusion in donation after circulatory death: A post hoc analysis of the Normothermic Ex Vivo Lung Perfusion as an Assessment of Extended/Marginal Donors Lungs trial.

OBJECTIVE: Donation after circulatory death (DCD) donors offer the ability to expand the lung donor pool and ex vivo lung perfusion (EVLP) further contributes to this ability by allowing for additional evaluation and resuscitation of these extended criteria donors. We sought to determine the outcomes of recipients receiving organs from DCD EVLP donors in a multicenter setting. METHODS: This was an unplanned post hoc analysis of a multicenter, prospective, nonrandomized trial that took place during 2011 to 2017 with 3 years of follow-up. Patients were placed into 3 groups based off procurement strategy: brain-dead donor (control), brain-dead donor evaluated by EVLP, and DCD donors evaluated by EVLP. The primary outcomes were severe primary graft dysfunction at 72 hours and survival. Secondary outcomes included select perioperative outcomes, and 1-year and 3-years allograft function and quality of life measures. RESULTS: The DCD EVLP group had significantly higher incidence of severe primary graft dysfunction at 72 hours (P = .03), longer days on mechanical ventilation (P < .001) and in-hospital length of stay (P = .045). Survival at 3 years was 76.5% (95% CI, 69.2%-84.7%) for the control group, 68.3% (95% CI, 58.9%-79.1%) for the brain-dead donor group, and 60.7% (95% CI, 45.1%-81.8%) for the DCD group (P = .36). At 3-year follow-up, presence observed bronchiolitis obliterans syndrome or quality of life metrics did not differ among the groups. CONCLUSIONS: Although DCD EVLP allografts might not be appropriate to transplant in every candidate recipient, the expansion of their use might afford recipients stagnant on the waitlist a viable therapy.

Extended post-ex vivo lung perfusion cold preservation predicts primary graft dysfunction and mortality: Results from a multicentric study.

BACKGROUND: Ex vivo lung perfusion (EVLP) allows for a reassessment of lung grafts initially deemed unsuitable for transplantation, increasing the available donor pool; however, this requires a pre- and post-EVLP period of cold ischemic time (CIT). Paucity of data exists on how the sequence of cold normothermic-cold preservations affect outcomes. METHODS: A total of 110 patients were retrospectively analyzed. Duration of 3 preservation phases was measured: cold pre-EVLP, EVLP, and cold post-EVLP. The donor and recipient clinical data were collected. Primary graft dysfunction (PGD) and survival were monitored. Risk of mortality or PGD was calculated using Cox proportional hazards and logistic regression models to adjust for baseline characteristics. RESULTS: Using the highest quartile, patients were stratified into extended vs non-extended pre-EVLP (<264 vs ≥264 minutes) and post-EVLP (<287 vs ≥287 minutes) CIT. The rates of 1-year mortality (8.4% vs 29.6%, p = 0.013), PGD 2-3 (20.5% vs 52%, p = 0.002), and PGD 3 (8.4% vs 29.6%, p = 0.005) at 72 hours were increased in the extended post-EVLP CIT group. After adjusting for baseline risk factors, the extended group remained an independent predictor of PGD ≥2 (odd ratio: 6.18, 95% CI: 1.88-20.3, p = 0.003) and PGD 3 (odd ratio: 20.4, 95% CI: 2.56-161.9, p = 0.004) at 72 hours and 1-year mortality (hazard ratio: 17.9, 95% CI: 3.36-95.3, p = 0.001). Cold pre-EVLP was not a significant predictor of primary outcomes. CONCLUSIONS: Extended cold post-EVLP preservation is associated with a risk for PGD and 1-year mortality. Pre-EVLP CIT does not increase mortality or high-grade PGD. These findings from a multicenter trial should caution on the implementation of extended cold preservation after EVLP.

Heart and Lung Transplants from HCV-Infected Donors to Uninfected Recipients.

BACKGROUND: Hearts and lungs from donors with hepatitis C viremia are typically not transplanted. The advent of direct-acting antiviral agents to treat hepatitis C virus (HCV) infection has raised the possibility of substantially increasing the donor organ pool by enabling the transplantation of hearts and lungs from HCV-infected donors into recipients who do not have HCV infection. METHODS: We conducted a trial involving transplantation of hearts and lungs from donors who had hepatitis C viremia, irrespective of HCV genotype, to adults without HCV infection. Sofosbuvir-velpatasvir, a pangenotypic direct-acting antiviral regimen, was preemptively administered to the organ recipients for 4 weeks, beginning within a few hours after transplantation, to block viral replication. The primary outcome was a composite of a sustained virologic response at 12 weeks after completion of antiviral therapy for HCV infection and graft survival at 6 months after transplantation. RESULTS: A total of 44 patients were enrolled: 36 received lung transplants and 8 received heart transplants. The median viral load in the HCV-infected donors was 890,000 IU per milliliter (interquartile range, 276,000 to 4.63 million). The HCV genotypes were genotype 1 (in 61% of the donors), genotype 2 (in 17%), genotype 3 (in 17%), and indeterminate (in 5%). A total of 42 of 44 recipients (95%) had a detectable hepatitis C viral load immediately after transplantation, with a median of 1800 IU per milliliter (interquartile range, 800 to 6180). Of the first 35 patients enrolled who had completed 6 months of follow-up, all 35 patients (100%; exact 95% confidence interval, 90 to 100) were alive and had excellent graft function and an undetectable hepatitis C viral load at 6 months after transplantation; the viral load became undetectable by approximately 2 weeks after transplantation, and it subsequently remained undetectable in all patients. No treatment-related serious adverse events were identified. More cases of acute cellular rejection for which treatment was indicated occurred in the HCV-infected lung-transplant recipients than in a cohort of patients who received lung transplants from donors who did not have HCV infection. This difference was not significant after adjustment for possible confounders. CONCLUSIONS: In patients without HCV infection who received a heart or lung transplant from donors with hepatitis C viremia, treatment with an antiviral regimen for 4 weeks, initiated within a few hours after transplantation, prevented the establishment of HCV infection. (Funded by the Mendez National Institute of Transplantation Foundation and others; DONATE HCV ClinicalTrials.gov number, NCT03086044.).

Posttransplant Lymphoproliferative Disorders in Epstein-Barr Virus Donor Positive/Recipient Negative Lung Transplant Recipients.

BACKGROUND: Epstein-Barr virus (EBV) donor positive/recipient negative (D+/R-) status is a significant risk factor for posttransplant lymphoproliferative disorder (PTLD) in lung transplant. There are, however, no studies that identify the risk factors for PTLD in the EBV D+/R- lung transplant population to guide the decision to proceed with an EBV-positive donor. METHODS: This was a retrospective cohort study of adults listed in the Scientific Registry of Transplant Recipients between May 5, 2005, and August 31, 2016. Cox proportional hazards models were used to assess the impact of EBV D+/R- status on the development of PTLD, the impact of PTLD on survival, and survival differences between EBV D+/R- and EBV D-/R- recipients. RESULTS: The incidence of PTLD was 6.2% (79 of 1,281) versus 1.4% (145 of 10,352) in EBV D+/R- versus all other recipients (adjusted odds ratio 4.0; 95% confidence interval: 2.8 to 5.9, p < 0.001). Among EBV D+/R- recipients, age less than 40 years and white race were associated with PTLD. The EBV D+/R- patients who had PTLD had increased adjusted risk of death (hazard ratio 1.91; 95% confidence interval: 1.35 to 2.71; p < 0.001). Compared with EBV D+/R- recipients, EBV D-/R- recipients did not have improved adjusted survival (hazard ratio 0.82; 95% confidence interval: 0.57 to 1.18; p = 0.30). CONCLUSIONS: Despite increased rates of PTLD and associated mortality in the EBV D+/R- population, EBV seronegative patients did not have worse mortality when transplanted with lungs from EBV seropositive donors compared with lungs from EBV seronegative donors. Consideration should be given for close monitoring for PTLD among EBV D+/R- recipients, particularly those who are white and less than 40 years of age.

Quantitative computed tomography assessment of bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a clinical manifestation of chronic allograft rejection following lung transplantation. We examined the quantitative measurements of the proximal airway and vessels and pathologic correlations in subjects with BOS. METHODS: Patients who received a lung transplant at the Brigham and Women's Hospital between December 1, 2002 and December 31, 2010 were included in this study. We characterized the quantitative CT measures of proximal airways and vessels and pathological changes. RESULTS: Ninety-four (46.1%) of the 204 subjects were included in the study. There was a significant increase in the airway vessel ratio in subjects who developed progressive BOS compared to controls and non-progressors. There was a significant increase in airway lumen area and decrease in vessel cross-sectional area in patients with BOS compared to controls. Patients with BOS had a significant increase in proximal airway fibrosis compared to controls. CONCLUSIONS: BOS is characterized by central airway dilation and vascular remodeling, the degree of which is correlated to decrements in lung function. Our data suggest that progressive BOS is a pathologic process that affects both the central and distal airways.

Predictors and outcomes of unplanned early rehospitalization in the first year following lung transplantation.

Unplanned early rehospitalization (UER), defined as an unscheduled admission within 30 days of a hospital discharge, is associated with graft loss and recipient mortality in some solid organ transplants but has not been investigated in lung transplant. In this retrospective study, we collected socio-demographic and clinical factors to determine predictors and outcomes of UER in the first year following lung transplantation. There were 193 patients who underwent lung transplantation and survived to discharge during the 7.9-year study period. There were 116 (60.1%) patients with at least one UER. Infections (32.8%) and post-surgical complications (11.8%) were the most common reasons for UER. On multivariate analysis, the strongest predictor of having an UER was discharge to a long-term acute care facility (odds ratio: 3.01, 95% confidence interval [CI] 1.46-6.20; P=.003). Patients with any UER in the first year following transplantation had worse adjusted survival (hazard ratio: 1.89, 95% CI 1.02-3.50; P=.04). It is unclear, however, to what extent UERs reflect preventable outcomes. Further large-scale, prospective research is needed to identify the extent to which certain types of UER are modifiable and to define patients at high-risk for preventable UER.

Aminocaproic acid for the management of bleeding in patients on extracorporeal membrane oxygenation: Four adult case reports and a review of the literature.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is associated with a significant risk of bleeding and thrombosis. Despite high rates of bleeding and bleeding-related mortality in patients on ECMO, there is little evidence available to guide clinicians in the management of ECMO-associated bleeding. METHODS: We report the use of aminocaproic acid in four patients with bleeding on ECMO and a review of the literature. RESULTS: High D-dimer levels and low fibrinogen levels suggested that an antifibrinolytic agent may be effective as an adjunct to control bleeding. After aminocaproic acid administration, bleeding was controlled in each patient as evidenced by clinical and laboratory parameters. One patient suffered a cardiac arrest and care was withdrawn. CONCLUSIONS: In patients on ECMO with evidence of fibrinolysis, aminocaproic acid may be an effective option to control bleeding and to stabilize clot formation.

Prevalence and outcome of lung cancer in lung transplant recipients.

BACKGROUND: Lung transplant is the only available therapy for patients with advanced lung disease. The goal of this study was to examine the prevalence, origin, management and outcome of lung cancer in recipients of lung transplant at our institution. METHODS: After institutional review board approval, we conducted a retrospective chart review of all lung transplantations in our institution from January 1990 until June 2012. RESULTS: The prevalence of lung cancer in the explanted lung was 6 (1.2%) of 462 and all cases were in subjects with lung fibrosis. All 4 subjects with lymph node involvement died of causes related to the malignancy. Nine (1.9%) of 462 patients were found to have bronchogenic carcinoma after lung transplant. The most common location was in the native lung in recipients of a single lung transplant (6 out of 9 patients). In one case, the tumor originated in the allograft and was potentially donor related. The median time to diagnosis after lung transplant was 28 months with a range from 9 months to 10 years. Median survival was 8 months, with tumors involving lymph nodes or distant metastases associated with a markedly worse prognosis (median survival 7 months) than stage I disease (median survival 27 months). CONCLUSIONS: The prevalence of lung cancer in lung transplant recipients is low. Using accepted donor screening criteria, donor derived malignancy is exceptionally rare. While stage I disease is associated with improved survival in this cohort, survival is still not comparable to that of the general population, likely influenced by the need for aggressive immune suppression.

Short telomeres, telomeropathy, and subclinical extrapulmonary organ damage in patients with interstitial lung disease.

BACKGROUND: Human telomere disease consists of a wide spectrum of disorders, including pulmonary, hepatic, and bone marrow abnormalities. The extent of bone marrow and liver abnormalities in patients with interstitial lung disease (ILD) and short telomeres is unknown. METHODS: The lung transplant clinic established a prospective protocol to identify short telomeres in patients with ILD not related to connective tissue disease or sarcoidosis. Patients with short telomeres underwent bone marrow biopsies, liver biopsies, or both as part of the evaluation for transplant candidacy. RESULTS: One hundred twenty-seven patients met ILD categorization for inclusion. Thirty were suspected to have short telomeres, and 15 had the diagnosis confirmed. Eight of 13 (53%) patients had bone marrow abnormalities. Four patients had hypocellular marrow associated with macrocytosis and relatively normal blood counts, which resulted in changes to planned immunosuppression at the time of transplant. Four patients with more severe hematologic abnormalities were not listed because of myelodysplastic syndrome (two); monoclonal gammopathy of unclear significance (one); and hypocellular marrow, decreased megakaryocyte lineage associated with thrombocytopenia (one). Seven patients underwent liver biopsies, and six had abnormal liver pathology. These abnormalities did not affect listing for lung transplant, and liver biopsies are no longer routinely obtained. CONCLUSIONS: Subclinical bone marrow and liver abnormalities can be seen in patients with ILD and short telomeres, in some cases in the absence of clinically significant abnormalities in peripheral blood counts and liver function tests. A larger study examining the implication of these findings on the outcome of patients with ILD and short telomeres is needed.

Impact of pretransplant anti-HLA antibodies on outcomes in lung transplant candidates.

RATIONALE: The prevalence of anti-HLA antibodies in lung transplant candidates and their impact on waitlist and transplant outcomes is not known. OBJECTIVES: We examined the prevalence of pretransplant anti-HLA antibodies at varying thresholds and evaluated their impact on outcomes before and after lung transplantation. METHODS: We performed a single-center retrospective cohort study including all patients listed for lung transplantation between January 2008 and August 2012. Per protocol, transplant candidates were assessed by solid phase LABscreen mixed Class I and II and LABscreen Single Antigen assays. MEASUREMENTS AND MAIN RESULTS: Among 224 patients, 34% had anti-HLA antibodies at mean fluorescent intensity (MFI) greater than or equal to 3,000 (group III), and 24% had antibodies at MFI 1,000 to 3,000 (group II). Ninety percent of the patients with pretransplant anti-HLA antibodies had class I antibodies, whereas only seven patients developed class II alone. Patients in group III were less likely to receive transplants than patients without any anti-HLA antibodies (group I) (45.5 vs. 67.7%, P = 0.005). Wait time to transplant was longer in group III than group I, although this difference did not meet statistical significance, and waitlist mortality was similar. Among transplant recipients, antibody-mediated rejection (AMR) was more frequent in group III than in group II (20% vs. 0%, P = 0.01) or group I (6.3%, P = 0.05). CONCLUSIONS: The presence of anti-HLA antibodies at the high MFI threshold (>3,000) was associated with lower transplant rate and higher rates of AMR. Screening for anti-HLA antibodies using the 3,000 MFI threshold may be important in managing transplant candidates and recipients.

Interstitial pneumonitis and the risk of chronic allograft rejection in lung transplant recipients.

BACKGROUND: The presence of interstitial pneumonitis (IP) on surveillance lung biopsy specimens in lung transplant recipients is poorly described, and its impact on posttransplant outcomes is not established. The following study assessed the association of posttransplant IP with the development of bronchiolitis obliterans syndrome (BOS). METHODS: We examined all recipients of primary cadaveric lung transplants at our institution between January 1, 2000, and December 31, 2007 (N = 145). Patients had bronchoscopies with BAL, and transbronchial biopsies performed for surveillance during posttransplant months 1, 3, 6, and 12 as well as when clinically indicated. Patients were given a diagnosis of IP if, in the absence of active infection and organizing pneumonia, they showed evidence of interstitial inflammation and fibrosis on two or more biopsy specimens. RESULTS: IP was a significant predictor of BOS (OR, 7.84; 95% CI, 2.84-21.67; P < .0001) and was significantly associated with time to development of BOS (hazard ratio, 3.8; 95% CI, 1.93-7.39; P = .0001) within the first 6 years posttransplant. The presence of IP did not correlate with a significantly higher risk of mortality or time to death. There was no association between the presence of IP and the development of or time to acute rejection. CONCLUSIONS: The presence of IP on lung transplant biopsy specimens suggests an increased risk for BOS, which is independent of the presence of acute cellular rejection.

A targeted peritransplant antifungal strategy for the prevention of invasive fungal disease after lung transplantation: a sequential cohort analysis.

BACKGROUND: Lung transplant recipients are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis and candidiasis. The antifungal strategy that optimally balances effective reduction of IFD with a minimum of toxicity remains undefined; universal triazole prophylaxis is common at lung transplantation (LT) centers, despite the well-known toxicities and costs of this approach. METHODS: We implemented an antifungal strategy in March 2007 targeted at LT recipients at highest risk for IFD based on our institutional epidemiology. All patients received inhaled amphotericin B during their initial LT hospitalization, bilateral lung transplant recipients received 7 to 10 days of micafungin, and only patients with growth of yeast or mold in their day-of-transplant cultures received further oral antifungal therapy tailored to their fungal isolate. RESULTS: IFD events were assessed in sequential cohorts composed of 82 lung transplant recipients before and 83 patients after the implementation of this targeted antifungal strategy. We observed a sharp decline in IFD; in the second cohort, 87%, 91%, and 96% of patients were free of IFD, invasive candidiasis, and invasive aspergillosis at 1 year. Only 19% of patients in the second cohort received systemic antifungal therapy beyond the initial LT hospitalization, and no patients experienced antifungal drug-related toxicity or IFD-associated mortality. CONCLUSIONS: The targeted antifungal strategy studied seems to be a reasonable approach to reducing post-LT IFD events while limiting treatment-related toxicities and costs.

Atrial arrhythmias after lung transplantation: epidemiology, mechanisms at electrophysiology study, and outcomes.

BACKGROUND: Atrial arrhythmias (AAs) including atrial fibrillation (AF) and atrial tachycardia (AT) are often observed after cardiothoracic surgery. Our aim was to evaluate the prevalence and mechanism of AAs after lung transplantation. METHODS AND RESULTS: All patients (n=127) after bilateral sequential lung transplantation followed at our institution over 20 years were included. All patients received postoperative rhythm monitoring and clinic visits with ECG at 1, 3, 6, and 12 months, or as needed. AAs occurred in 40 of 127 (31.5%) patients over 4.2+/-4.1 years. AA prevalence at postoperation and 1, 3, 6, 12, and >12 months was 24%, 11%, 3%, 2%, 4%, and 11%, respectively. Early AAs were predominantly AF, whereas all AAs >12 months were AT. Time to first AF versus AT was 11+/-9 versus 1485+/-2462 days (P=0.09). Male sex, age, and preoperative AA predicted any early (<3 months) AA but did not predict late AA. Early AA did not predict late AT. In 4 patients with drug-resistant AT, electrophysiology studies found AT involving the pulmonary vein/left atrium anastomoses in 3 patients, including donor-to-recipient conduction in 1, border zone macroreentry in 2, and cavotricuspid isthmus dependent flutter in 1; all patients were successfully treated with ablation. CONCLUSIONS: AAs after lung transplantation are common. Although AF is common early, AF is rare after healing of left atrial incisions, which probably result in surgical pulmonary vein isolation with rare exception. This raises the question of whether additional surgical or ablation lines at the time of lung transplantation would prevent late AA.

Controlled antegrade single lung reperfusion during double lung transplant.

Prompt controlled reperfusion of a pulmonary allograft in a sequential double lung transplant may correct cellular ischemia prior to exposure to full hydrostatic pressures and minimize organ dysfunction. We reviewed the process of a sequential double lung transplant and describe the technique of controlled antegrade graft reperfusion of the initial implant as performed at our institution.

MDCT evaluation of central airway and vascular complications of lung transplantation.

OBJECTIVE: The purpose of this article is to illustrate the spectrum of central airway and vascular complications in lung transplantation using MDCT, with an emphasis on the usefulness of advanced postprocessing techniques. CONCLUSION: MDCT is an invaluable tool in the diagnosis, evaluation, and posttreatment assessment of central airway and vascular complications in lung transplant recipients. Advanced postprocessing techniques provide complementary information that is visually accessible and anatomically meaningful for the clinician.

Successful treatment of refractory bleeding after bridging from acute to chronic left ventricular assist device support with recombinant activated factor VII.

Cardiac surgery often is associated with a significant disruption of the coagulation system, particularly in high risk patients such as those undergoing placement of ventricular assist devices. This type of severe coagulopathy can lead to life threatening bleeding that can require massive transfusions to restore hemostasis. Recently, recombinant activated factor VII (rFVlla) has been +used as an alternative to massive transfusion for the treatment of refractory bleeding in several patient populations, including cardiac surgery patients. In the case reported here, the patient's risk was compounded by multiple operations in a short period of time and circulatory collapse that was initially managed with a shortterm left ventricular assist device. After multiple failed attempts at weaning the patient from circulatory assistance, he was taken back to the operating room for conversion to a chronic, implantable device. This procedure was complicated by a severe coagulopathy secondary to a myriad of factors commonly encountered after the use of cardiopulmonary bypass. The administration of rFVlla resulted in a rapid cessation of bleeding without thrombotic complications. This is the first case reported involving an acute to chronic bridge patient. Despite the anecdotal success of rFVlla, further clinical research is needed to establish both the safety and economic feasibility of this agent.

Recombinant factor VIIa for refractory bleeding following orthotopic heart transplantation.

OBJECTIVE: To report a case of successful use of recombinant factor VIIa (rFVIIa) for the treatment of refractory bleeding in a patient undergoing orthotopic heart transplantation. CASE SUMMARY: A 57-year-old white male with idiopathic cardiomyopathy was taken to the operating room for explantation of his left-ventricular assist device and orthotopic heart transplantation. He experienced excessive generalized oozing that required transfusions of multiple units of blood products and significant amounts of Cellsaver (washed red blood cells via autotransfusion) without achieving adequate hemostasis. After ruling out any obvious surgical sources of bleeding and attempting to correct all coagulation deficiencies, the clinicians administered rFVIIa 90 microg/kg. The oozing rapidly declined to a negligible level, chest tubes and sternal wires were placed, and the chest was closed. The patient was on minimal inotropic support and was transferred to the intensive care unit in stable condition. DISCUSSION: Cardiac surgery is often associated with significant disruption of the coagulation system, particularly in high-risk patients, such as those undergoing removal of a ventricular assist device and subsequent orthotopic heart transplantation. This can lead to life-threatening bleeding that can require multiple hemostatic agents and significant transfusions to restore hemostasis. Recently, rFVIIa has been utilized as an alternative to massive transfusion for treatment of refractory bleeding in several patient populations, including some cardiac surgery patients. CONCLUSIONS: rFVIIa appears to be a viable option as rescue therapy for treatment of refractory bleeding following orthotopic heart transplantation. Despite the anecdotal success of rFVIIa in this setting, further clinical research is needed.

Thin-filament-based modulation of contractile performance in human heart failure.

BACKGROUND: The contribution of the sarcomere's thin filament to the contractile dysfunction of human cardiomyopathy is not well understood. METHODS AND RESULTS: We have developed techniques to isolate and functionally characterize intact (native) thin filaments obtained from failing and nonfailing human ventricular tissue. By use of in vitro motility and force assays, native thin filaments from failing ventricular tissue exhibited a 19% increase in maximal velocity but a 27% decrease in maximal contractile force compared with nonfailing myocardium. Native thin filaments isolated from human myocardium after left ventricular assist device support demonstrated a 37% increase in contractile force. Dephosphorylation of failing native thin filaments resulted in a near-normalization of thin-filament function, implying a phosphorylation-mediated mechanism. Tissue expression of the protein kinase C isoforms alpha, beta1, and beta2 was increased in failing human myocardium and reduced after left ventricular assist device support. CONCLUSIONS: These novel findings demonstrate that (1) the thin filament is a key modulator of contractile performance in the failing human heart, (2) thin-filament function is restored to near normal levels after LVAD support, and (3) the alteration of thin-filament function in failing human myocardium is mediated through phosphorylation, most likely through activation of protein kinase C.