Nuances in the interpretation and utility of donor-derived cell-free DNA in lung transplantation following allogeneic hematopoietic stem cell transplantation - Case report.

Respiratory complications following allogeneic HSCT can lead to severe morbidity and mortality. Lung transplantation (LT) is a potential treatment for select patients with late-onset non-infectious pulmonary complications post-HSCT. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for monitoring the health of allografts following LT. However, its utility in a multi-genome setting of LT after HSCT has not yet been clinically validated. Here we describe a case of a 75-year-old, male patient who underwent single-lung transplantation for BOS related to chronic GVHD and presented with persistently elevated dd-cfDNA levels. In a surveillance biopsy, the patient was diagnosed with mild acute cellular rejection at three months. The patient's lung function remained stable, and the reported dd-cfDNA levels decreased after the rejection episode but remained elevated above levels that would be considered quiescent for LT alone. In this unique setting, as 3 different genomes contributed to the dd-cfDNA% reported value, valuable insight was obtained by performing further analysis to separate the specific SNPs to identify the contribution of recipient, lung-donor, and HSCT-donor cfDNA. This study highlights the potential utility of dd-cfDNA in the multi-genome setting of lung transplant post-HSCT, nuances that need to be considered while interpreting the results, and its value in monitoring lung rejection.

Pulmonary transplant complications: a radiologic review.

Lung transplantation has become the definitive treatment for end stage respiratory disease. Numbers and survival rates have increased over the past decade, with transplant recipients living longer and with greater comorbidities, resulting in greater complexity of care. Common and uncommon complications that occur in the immediate, early, intermediate, and late periods can have significant impact on the course of the transplant. Fortunately, advancements in surgery, medical care, and imaging as well as other diagnostics work to prevent, identify, and manage complications that would otherwise have a negative impact on survivability. This review will focus on contextualizing complications both categorically and chronologically, with highlights of specific imaging and clinical features in order to inform both radiologists and clinicians involved in post-transplant care.

Relative Change in Donor-Derived Cell-free DNA is Superior to Absolute Values for Diagnosis of Acute Lung Allograft Dysfunction.

Donor-derived cell-free DNA (dd-cfDNA%) is a biomarker of early acute lung allograft dysfunction (ALAD), with a value of ≥1.0% indicating injury. Whether dd-cfDNA% is a useful biomarker in patients >2 y posttransplant is unknown. Our group previously demonstrated that median dd-cfDNA% in lung recipients ≥2 y posttransplant without ALAD was 0.45%. In that cohort, biologic variability of dd-cfDNA% was estimated by a reference change value (RCV) of 73%, suggesting that change exceeding 73% may be pathologic. In this study, we aimed to determine whether dd-cfDNA% variability or absolute thresholds are optimal for detecting ALAD. Methods: We prospectively measured plasma dd-cfDNA% every 3 to 4 mo in patients ≥2 y post-lung transplant. ALAD was defined as infection, acute cellular rejection, possible antibody-mediated rejection, or change in forced expiratory volume in 1 s >10%, and was adjudicated retrospectively. We analyzed area under the curve for RCV and absolute dd-cfDNA% and reported performance of RCV ≥73% versus absolute value >1% for discriminating ALAD. Results: Seventy-one patients had ≥2 baseline measurements of dd-cfDNA%; 30 developed ALAD. RCV of dd-cfDNA% at ALAD had a greater area under the receiver operator characteristic curve than absolute dd-cfDNA% values (0.87 versus 0.69, P = 0.018). Test characteristics of RCV >73% for ALAD diagnosis were sensitivity 87%, specificity 78%, positive predictive value 74%, and negative predictive value 89%. In contrast, dd-cfDNA% ≥1% had sensitivity 50%, specificity 78%, positive predictive value 63%, and negative predictive value 68%. Conclusions: Relative change in dd-cfDNA% has improved test characteristics for diagnosing ALAD compared with absolute values.

Status Epilepticus in Post-Transplantation Hyperammonemia Involves Careful Metabolic Management.

Hyperammonemia is a condition that may result after solid organ transplantation, particularly lung transplantation. However, it is very uncommon for this presentation to occur more than 30 days post-transplantation. Hyperammonemia and the resulting encephalopathy typically manifest with altered sensorium, a clinical situation which is not often included in the differential diagnosis of presumed nonconvulsive status epilepticus (NCSE). Seizures are common among this subset of patients with hyperammonemia and may be refractory to traditional treatments. Evidence of elevated intracranial pressure by invasive monitoring and neuroimaging findings of diffuse cerebral edema are commonly reported. Here we examine the therapeutic importance of identifying the specific cause of hyperammonemic encephalopathy, a condition which may result in status epilepticus and ultimately cerebral edema or even brain death.

Clinical Presentation and Treatment of High-Risk Sarcoidosis.

Sarcoidosis is a multisystem disease of unknown cause with heterogeneous clinical manifestations and variable course. Spontaneous remissions occur in some patients, whereas others have progressive disease impacting survival, organ function, and quality of life. Four high-risk sarcoidosis phenotypes associated with chronic inflammation have recently been identified as high-priority areas for research. These include treatment-refractory pulmonary disease, cardiac sarcoidosis, neurosarcoidosis, and multiorgan sarcoidosis. Significant gaps currently exist in the understanding of these high-risk manifestations of sarcoidosis, including their natural history, diagnostic criteria, biomarkers, and the treatment strategy, such as the ideal agent, optimal dose, and treatment duration. The use of registries with well-phenotyped patients is a critical first step to study high-risk sarcoidosis manifestations systematically. We review the diagnostic and treatment approach to high-risk sarcoidosis manifestations. Appropriately identifying these disease subgroups will help enroll well-phenotyped patients in sarcoidosis registries and clinical trials, a necessary step to narrow existing gaps in understanding of this enigmatic disease.

An obligatory role for club cells in preventing obliterative bronchiolitis in lung transplants.

Obliterative bronchiolitis (OB) is a poorly understood airway disease characterized by the generation of fibrotic bronchiolar occlusions. In the lung transplant setting, OB is a pathological manifestation of bronchiolitis obliterans syndrome (BOS), which is a major impediment to long-term recipient survival. Club cells play a key role in bronchiolar epithelial repair, but whether they promote lung transplant tolerance through preventing OB remains unclear. We determined if OB occurs in mouse orthotopic lung transplants following conditional transgene-targeted club cell depletion. In syngeneic lung transplants club cell depletion leads to transient epithelial injury followed by rapid club cell-mediated repair. In contrast, allogeneic lung transplants develop severe OB lesions and poorly regenerate club cells despite immunosuppression treatment. Lung allograft club cell ablation also triggers the recognition of alloantigens, and pulmonary restricted self-antigens reported associated with BOS development. However, CD8+ T cell depletion restores club cell reparative responses and prevents OB. In addition, ex-vivo analysis reveals a specific role for alloantigen-primed effector CD8+ T cells in preventing club cell proliferation and maintenance. Taken together, we demonstrate a vital role for club cells in maintaining lung transplant tolerance and propose a new model to identify the underlying mechanisms of OB.

Bronchiolitis obliterans syndrome-free survival after lung transplantation: An International Society for Heart and Lung Transplantation Thoracic Transplant Registry analysis.

BACKGROUND: Lung transplant (LTx) recipients have low long-term survival and a high incidence of bronchiolitis obliterans syndrome (BOS). However, few long-term, multicenter, and precise estimates of BOS-free survival (a composite outcome of death or BOS) incidence exist. METHODS: This retrospective cohort study of primary LTx recipients (1994-2011) reported to the International Society of Heart and Lung Transplantation Thoracic Transplant Registry assessed outcomes through 2012. For the composite primary outcome of BOS-free survival, we used Kaplan-Meier survival and Cox proportional hazards regression, censoring for loss to follow-up, end of study, and re-LTx. Although standard Thoracic Transplant Registry analyses censor at the last consecutive annual complete BOS status report, our analyses allowed for partially missing BOS data. RESULTS: Due to BOS reporting standards, 99.1% of the cohort received LTx in North America. During 79,896 person-years of follow-up, single LTx (6,599 of 15,268 [43%]) and bilateral LTx (8,699 of 15,268 [57%]) recipients had a median BOS-free survival of 3.16 years (95% confidence interval [CI], 2.99-3.30 years) and 3.58 years (95% CI, 3.53-3.72 years), respectively. Almost 90% of the single and bilateral LTx recipients developed the composite outcome within 10 years of transplantation. Standard Registry analyses "overestimated" median BOS-free survival by 0.42 years and "underestimated" the median survival after BOS by about a half-year for both single and bilateral LTx (p < 0.05). CONCLUSIONS: Most LTx recipients die or develop BOS within 4 years, and very few remain alive and free from BOS at 10 years post-LTx. Less inclusive Thoracic Transplant Registry analytic methods tend to overestimate BOS-free survival. The Registry would benefit from improved international reporting of BOS and other chronic lung allograft dysfunction (CLAD) events.

A case of pancake kidney with a single ureter in the retroperitoneal space.

The pancake kidney (PK) is a rare type of renal anomaly in which both kidneys completely fuse without an isthmus. In the previous reports, PKs have double ureters and are located in the pelvic cavity. We encountered a rare case of PK with a single ureter, which is located in the left retroperitoneal space, in a 95-year-old female cadaver, which was detected during a dissection course. In our case, the major calyces joined to form a single renal pelvis, which continued as a single ureter. To the best of our knowledge, this is the first report on PK with a single ureter that is located not in the pelvic cavity but in the retroperitoneal space. The knowledge of such anomalous presentation is important to avoid any complications during retroperitoneal surgery.

Examining ABO compatible donors in double lung transplants during the era of lung allocation score.

BACKGROUND: The short-term and long-term effect of using ABO compatible donors in the era of lung allocation score is unknown. This study determined if carefully selected ABO compatible donors could be used in double lung transplantation (DLT) with good outcomes. METHODS: The United Network for Organ Sharing database was retrospectively reviewed for adult DLT from May 2005 to December 2011. RESULTS: Of 6,655 double lung transplants, 493 (7.4%) were with ABO compatible donors and 6,162 (92.6%) were with ABO identical donors. In multivariate analysis, use of ABO compatible donors was not associated with mortality at 30 days (HR, 1.16; 95% CI, 0.76 to 1.79, p = 0.49), 1 year (HR, 1.10; 95% CI, 0.86 to 1.42, p = 0.46), and 5 years (HR, 1.06; 95% CI, 0.83 to 1.34, p = 0.65). Variables associated with mortality at 5 years were donor female sex, donor age 60 years or greater, prolonged ischemic time, increasing recipient creatinine, recipient age, race mismatch, and mechanical ventilation or extracorporeal membrane oxygenation as a bridge to transplantation. Length of stay was longer in the ABO compatible group (30.9 vs 25.9 days, p = 0.001). Acute rejection episodes on index hospitalization (8.8 vs. 8.9%, p = 1.00), peak posttransplant forced expiratory volume in 1 second (FEV1) (82.7 vs 79.7%, p = 0.053), and decrement in FEV1 over time were not different (p = 0.13). Freedom from bronchiolitis obliterans syndrome was similar (1,475 vs 1,454 days, p = 0.17). CONCLUSIONS: The use of ABO compatible donors in the era of lung allocation score was not associated with short-term or long-term mortality and resulted in equivalent posttransplant lung function. A DLT with carefully selected ABO compatible donors can result in excellent outcomes.

Single-lung transplantation with ABO-compatible donors results in excellent outcomes.

BACKGROUND: The goal of this study was to determine if carefully selected ABO-compatible donors in single-lung transplantation results in acceptable outcomes. METHODS: The United Network for Organ Sharing database was reviewed for adult single-lung transplant recipients from May 2005 to December 2011. Recipients of lungs from ABO-compatible donors were compared with those of ABO-identical donors. Mortality was examined with risk-adjusted multivariable Cox proportional hazards regression using significant univariate predictors. RESULTS: Of 3,572 single-lung transplants, 342 (9.6%) were from ABO-compatible donors. The two groups were evenly matched in recipient age (60.8 vs 60.2 years, p = 0.28), male gender (61.8% vs 58.2%, p = 0.10), lung allocation score (43.4 vs 42.6, p = 0.32), forced expiratory volume in 1 second (FEV1; 41.2% vs 40.8%, p = 0.32), and ischemic time (4.2 vs 4.0 hours, p = 0.09), and donor age (34.4 vs 32.9, p = 0.07) and male gender (61.5 vs 65.5, p = 0.14). ABO-compatible donors were less likely to be race mismatched (58.3% vs 50.9%, p = 0.01). Median survival was not different (1,284.0 vs 1,540 days, p = 0.39). On multivariate analysis, lungs from ABO-compatible donors were not associated with mortality (hazard ratio, 1.02; 95% confidence interval, 0.85-1.22; p = 0.86). Prolonged ischemic time, increasing recipient creatinine, increasing recipient age, race mismatch, class I plasma reactive antigen panel > 10%, and the use of mechanical ventilation or extracorporeal membrane oxygenation were associated with mortality. Peak post-transplant FEV1 (64.5% vs 64.0%, p = 0.69) and decrement in FEV1 over time were similar (p = 0.82). CONCLUSIONS: This large multi-institutional analysis of ABO-compatible donors in single-lung transplantation demonstrates that careful selection of ABO-compatible donors results in excellent outcomes.