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Exosomes isolated from plasma of lung transplant recipients with allograft injury contain donor-derived lung self-antigens (collagen V and Kα1 tubulin) and human leukocyte antigen (HLA) molecules. We present a case of a 76-year-old, female lung transplant recipient treated for acute cellular rejection with methylprednisolone and anti-thymocyte globulin, who subsequently contracted SARS-CoV-2 and developed a sharp increase in the mean fluorescent intensity of anti-HLA antibodies. Analysis of circulating exosomes during rejection, but before SARS-CoV-2 infection, revealed the presence of lung self-antigens and HLA class II molecules. After the patient contracted SARS-CoV-2, exosomes with the SARS-CoV-2 spike protein were also found. After resolution of infectious symptoms, exosomes with SARS-CoV-2 spike protein were no longer detected; however, exosomes with lung self-antigens and HLA class II molecules persisted, which coincided with a progressive decline in spirometric flows, suggesting chronic lung allograft dysfunction. We propose that the analysis of circulating exosomes may be used to detect allograft injury mediated by both rejection and infection. Furthermore, the detection of exosomes containing viral proteins may be helpful in identifying allograft injury driven by viral pathogens., (© 2020 Wiley Periodicals LLC.)

Background: Skin cancer is common after solid organ transplantation, but few have investigated it after lung transplant (LTx)., Objective: We assessed incidence and predictors of non-melanoma skin cancer (NMSC) post-LTx., Methods: We studied patients who underwent LTx at our center from 2012 to 2015., Results: Of 287 patients, mean age was 59.6 ± 11 years, 170 (59.2%) were men, and 231 (80.5%) were white. Seventy-six (26.5%) developed NMSC over a median follow-up of 32 months (IQR, 23-45). Of those with NMSC, 37% developed subsequent skin cancer of the same type. Independent predictors of decreased odds of NMSC and squamous cell carcinoma (SCC) were non-white race (P = .002; P = .003) and body mass index >30 kg/m 2 compared with underweight patients (P = .001, P = .009). Patients with skin cancer pre-LTx had higher risk of post-LTx skin cancer (P = .02). Voriconazole use ≥100 days was associated with increased risk of SCC (P = .03), but not increased risk of basal cell carcinoma. Out of 76, 4 (5.3%) died from skin cancer., Limitations: Retrospective, single-center study., Conclusion: Squamous cell carcinoma risk post-LTx may increase with prolonged voriconazole use in white patients with pre-LTx history of skin cancer, whereas excess body weight may be protective from NMSC. Regular pre- and post-LTx skin cancer screenings and guidelines are warranted., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Chronic lung allograft dysfunction (CLAD) is nonreversible and remains the biggest obstacle to long-term survival after lung transplantation (LTx). Retransplantation is the sole definitive therapeutic option for CLAD. We analyzed our single-center experience with retransplantation as a treatment option for CLAD., Methods: From March 1, 2010, to May 31, 2016, 419 consecutive patients underwent LTx at our institution; 29 of these procedures were retransplantations for CLAD. We analyzed demographic characteristics, lung allocation score, operation type, length of stay, and perioperative outcomes. Actuarial survival was estimated using Kaplan-Meier survival curves., Results: In total, 29 of 419 patients (6.9%) underwent retransplantation for CLAD. Median time from primary LTx to retransplantation was 1,163 days (range: 304 to 3,971 days). Patients undergoing retransplantation were younger and had higher lung allocation scores than primary transplantation patients. Most LTx procedures were bilateral (93% of retransplantations, 95% of primary LTx). Rates of cardiopulmonary bypass, extracorporeal membrane oxygenation support for severe primary graft dysfunction, and re-exploration for bleeding were higher in retransplantation patients (p = 0.010, p = 0.019, and p = 0.029, respectively). One- and 5-year survival rates in the retransplantation group were similar to those of the primary LTx group (89.2% and 64.3% versus 89.7% and 58.2%, respectively; p = 0.79)., Conclusions: Lung retransplantation is a viable treatment option for CLAD after LTx. In this study, retransplantation patients were younger, had higher lung allocation scores, and were more likely to require cardiopulmonary bypass and postoperative extracorporeal membrane oxygenation support than primary LTx patients. Postoperative length of stay and short- and mid-term survival were comparable with those of primary LTx patients., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The immunological role of exosomes in allograft rejection remains unknown. We sought to determine whether exosomes are induced during lung allograft rejection and to define the antigenic compositions of HLA, lung-associated self-antigens (SAgs) and microRNAs (miRNAs). Exosomes were isolated from sera and bronchoalveolar lavage fluid from 30 lung transplant recipients (LTxRs) who were stable or who had acute rejection (AR) or bronchiolitis obliterans syndrome (BOS). Exosomes were defined by flow cytometry for CD63 and western blotting for annexin V SAgs, collagen V (Col-V) and Kα1 tubulin were examined by electron microscopy; miRNAs were profiled by a miRNA array. Donor HLA and SAgs were detected on exosomes from LTxRs with AR and BOS but not from stable LTxRs. Exosomes expressing Col-V were isolated from sera from LTxRs 3 mo before AR and 6 mo before BOS diagnosis, suggesting that exosomes with SAgs may be a noninvasive rejection biomarker. Exosomes isolated from LTxRs with AR or BOS also contained immunoregulatory miRNAs. We concluded that exosomes expressing donor HLA, SAgs and immunoregulatory miRNAs are present in the circulation and local site after human lung transplantation and play an important role in the immune pathogenesis of acute allograft rejection and BOS., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Rarely, malignancies are incidentally detected in lung transplant (LT) explants. These can remain unidentified before LT due to significant architectural distortion of the lung parenchyma, despite appropriate radiographic surveillance. We present the case of a 74-year-old man with history of bilateral LT (03/2021), complicated by grade 2 primary graft dysfunction, for fibrotic hypersensitivity pneumonitis after which a high-grade neuroendocrine carcinoma was unexpectedly found in the right explanted lung. The tumor was 2.1 cm and 3/11 peribronchial lymph nodes were positive for metastatic carcinoma. The left lung explant was negative for malignancy. The tumor was strongly positive for TTF-1 and synaptophysin (Figure 1) with dot-like positivity of the pancytokeratin (AE1/AE3) and CAM 5.2 stains. Tumor cells were negative for CD45, PHH3 demonstrated >50 mitoses/10 high-power fields, and MIB-1 highlighted approximately 60% of tumor nuclei. Whole-body imaging was negative for other masses or acute processes. Maintenance immunosuppression was decreased, and the patient was discharged after LT in stable condition with need for outpatient oncology follow-up. Given the aggressive nature of the explant tumor, the patient decided to pursue adjuvant chemotherapy after recovery from the early post-LT period. The patient received 2 cycles of carboplatin/etoposide, but further treatment was stopped due to severe pancytopenia and need for blood products including platelets. At 6 months post-LT, allograft function is stable - FEV 1 at 2.56 L (88%) - with no evidence of acute cellular rejection or antibody-mediated rejection. There is no evidence of cancer recurrence. This is a rare case of high-grade neuroendocrine carcinoma in a lung explant after LT. Recommended etoposide/platinum-based chemotherapy may be limited by adverse effects. Prognosis and feasibility of adjuvant chemotherapy after LT is insufficiently understood. [ABSTRACT FROM AUTHOR]

Progressive multifocal leukoencephalopathy (PML) is a demyelinating brain disease caused by reactivation of JC virus in immunocompromised patients. PML typically manifests with subacute neurologic deficits including altered mental status, motor deficits, limb ataxia, gait ataxia, and visual symptoms. We report an atypical presentation of PML in a lung transplant recipient (LTR). A 71-year-old LTR received rituximab induction followed by a combination of mycophenolate mofetil, tacrolimus, and prednisone. He had a single episode of minimal acute cellular rejection early after LT, but never required significantly augmented immunosuppression. Notably, he had mild leukopenia throughout his post-LT course (WBC count 3-4 thousand/µL), and he had no response to 4 doses of the Pfizer SARS-CoV-2 vaccine, suggesting advanced immunosuppression. At 14 months after LT, the patient reported progressive anomia and aphasia, but no other neurologic deficits. MRI showed an abnormal increased T2/FLAIR signal in the left posterior parieto-occipital subcortical white matter, involving subcortical U fibers, characteristic of PML (Figure A, C). Serum JC virus PCR showed low-level viremia, but CSF from 2 lumbar punctures was PCR negative. Thus, he was diagnosed with possible PML, and immunosuppression was narrowed to a combination of tacrolimus (goal trough 4-6) and prednisone, 5 mg daily. Despite reduced immunosuppression, a repeat MRI 2 months after the initial diagnosis showed worsening PML (Figure B, D) and his symptoms progressed to severe anomia, aphasia, and cortical blindness, but still no motor deficits. PML is a rare, albeit well described, complication of LT, but presentation with only anomia and aphasia is unusual. Without CSF viral isolation, a definitive diagnosis requires brain tissue; however, MRI changes involving subcortical U fibers in the parieto-occipital area are highly characteristic. Early recognition allows for expeditious management. [ABSTRACT FROM AUTHOR]

Patients with respiratory failure (RF) who are hospitalized at the time of lung transplant (LTx) have higher post-LTx morbidity and mortality than those who are well enough to remain at home. Complications may be even worse in patients transplanted for COVID-19 (C19), as they are commonly critically ill having endured prolonged mechanical ventilation, ECMO support, myopathy, malnutrition, and superimposed infections. In a retrospective cohort study, we compared inpatient lung transplant recipients (LTxRs) transplanted for C19 vs. other underlying restrictive lung diseases (RLDs) After IRB approval, patients who underwent inpatient LTx between 1/1/2014 and 8/31/2021 were categorized by indication: C19 or RLD. We excluded LTxRs <18 years old, a primary indication for LTx other than UNOS disease group D, and redo LTx. Primary outcomes were postoperative morbidity and 90-day survival. Out of 163 inpatient LTxRs, 141 met inclusion criteria: 11 (7.8%) with C19 and 130 (92.2%) with RLD. LTxRs with C19 were younger, had a longer pre-LTx hospital stay, and more likely needed pre-LTx mechanical ventilation and ECMO support. LTxRs with C19 were also more likely to have severe adhesions intraoperatively and their chest was more commonly left open after LTx due to a perceived risk of ongoing bleeding. In addition, LTxRs with C19 had a higher prevalence of PGD3 at 72 hours and longer post-LTx hospital stays and trended toward longer post-LTx mechanical ventilation and need for inpatient rehabilitation. The 2 groups had similar 90-day survival (C19, 100% vs. RLD, 95.4%, p=0.472), however, LTxRs with C19 had a higher incidence of acute cellular rejection and DSA production (>2,000 MFI) within 6 months of transplant. LTxRs with C19 are typically sicker and have more post-LTx complications than LTxRs with RLD hospitalized at the time of LTx. However, 90-day survival is comparable and high in both groups. Long-term follow-up is needed. [ABSTRACT FROM AUTHOR]

Restrictive allograft syndrome is an aggressive variant of CLAD characterized by progressive restrictive ventilatory decline and persistent pleuro-parenchymal changes on chest CT. We identified 3 lung transplant recipients (LTRs) with a persistent restrictive ventilatory defect due to pleural thickening, effusions, plate-like and rounded atelectasis, but no pleuro-parenchymal fibrosis. 1) A 67-year-old bilateral LTR developed a rapidly progressive restrictive ventilatory defect, pleural thickening, bilateral pleural effusions, a pericardial effusion, and plate-like and rounded atelectasis 38 months post-LT. Bronchoscopy with lavage (BAL) and biopsy showed no evidence of infection or acute cellular rejection (ACR). Multiple thoracenteses did not improve spirometric flows, and pleural fluid analysis revealed a transudative lymphocyte predominance. Cardiac MRI showed anterior pericardial thickening; however, functional findings did not meet criteria for constrictive pericarditis. The patient died 3 months after his initial drop in FEV1. 2) A 72-year-old right, single LTR developed a gradually progressive restrictive ventilatory defect, a right pleural effusion, pleural thickening, and plate-like and rounded atelectasis within the allograft 6 months post-LT. Bronchoscopy with BAL and biopsy showed no evidence of infection or ACR. Multiple thoracenteses did not improve spirometric flows, and pleural fluid analysis revealed a transudative lymphocyte predominance. His FEV1 rapidly declined 14 months post-LT and he died 4 months later. 3) A 63-year-old bilateral LTR developed a gradually progressive restrictive ventilatory defect, bilateral loculated pleural effusions, pleural thickening, and plate-like and rounded atelectasis 21 months post-LT. Bronchoscopy with BAL and biopsy showed no evidence of infection or ACR. Multiple thoracenteses did not improve spirometric flows, and pleural fluid analysis revealed a transudative lymphocyte predominance. The patient remains alive 25 months post-LT, however, his FEV1 is at its nadir with a 25% decline from baseline. We hypothesize the presentation of these patients represents a distinct CLAD phenotype characterized by progressive restriction due to pleural inflammation, lymphocyte-predominant pleural effusions, resultant compressive atelectasis, and eventual respiratory failure. [ABSTRACT FROM AUTHOR]

Pet ownership is common in the United States, with 38.4% of households owning dogs, according to the American Veterinary Medical Association. Zoonotic infections are rare, but can cause serious disease, particularly in immunocompromised hosts. Capnocytophaga species are gram-negative, facultative anaerobic bacteria that are usually transmitted to humans from dogs but may also be human oral cavity commensals. They can cause rare but fulminant infections with a mortality rate of 10-30%. We report a case of capnocytophaga in a lung transplant recipient (LTR). A 72-year-old LTR on a standard immunosuppressive regimen with tacrolimus, mycophenolate mofetil, and prednisone reported right-sided back pain 2 years after transplantation. Computed tomography (CT) revealed a moderate right pleural effusion without lung parenchymal abnormalities. Pleural studies were exudative with an LDH of 740 units/L, total protein of 2.7 g/dL, and glucose of 89 mg/dL. All pleural fluid cultures were negative. His serum procalcitonin was marginally elevated at 0.2 ng/mL and his white blood cell count was normal (4.0 thousand/uL). He was subsequently hospitalized, underwent bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies, and was empirically treated with high-dose corticosteroids for presumed acute cellular rejection. The day after hospital discharge, capnocytophaga grew in BAL fluid cultures. He was readmitted to the hospital for chest tube drainage, intrapleural tissue plasminogen activator infusion to break up loculations, and a 4-week course of ceftriaxone. With antimicrobial therapy, the patient recovered clinically; however, his right lung remained trapped and a thick pleural rind was identified on CT. Upon further history, the patient and his wife reported owning 2 Pekingese-Poodle mix dogs; however, they were meticulous about avoiding contact with the dogs' saliva. Capnocytophaga infection in LTRs is rare, but due to its propensity to result in severe disease among immunosuppressed patients, accurate identification and prompt treatment is required. Transplant recipients need to be counseled regarding risk of contracting zoonotic infections from household pets so they can take appropriate preventative measures. However, despite best efforts, as in the case of this patient, these infections can still occur. [ABSTRACT FROM AUTHOR]

Prior to the COVID-19 (C19) pandemic, adult respiratory distress syndrome (ARDS) was an unusual indication for lung transplant (LT); thus, short- and long-term outcomes data are lacking. As the pandemic continues, there is an increased need for post-LT data. Thus, we report our single-center experience transplanting 11 patients for C19 ARDS. We conducted a chart review of LT recipients (LTRs) transplanted for C19 ARDS between 8/1/21 and 7/31/21. Descriptive statistics were used. Most LTRs were male (82%, n=9). The median age at LT, body mass index, and lung allocation score were 47 (43, 54) years, 28.9 (26, 30) kg/m2, and 84.5 (60, 88), respectively. The median interval from initial hospitalization to listing and listing to LT was 119 (97, 124) and 5 (4, 11) days, respectively. Pretransplant COVID-related morbidities included venous thromboembolism (55%, n=6), hemorrhage requiring transfusion (36%, n=4), pneumothorax (55%, n=6), bacterial pneumonia (82%, n=9), bacteremia (45%, n=5), fungemia (36%, n=4), renal failure requiring renal replacement therapy (RRT; 9%, n=1), cerebrovascular event (9%, n=1), and musculoskeletal weakness (100%, n=11). Most patients required mechanical ventilation (91%, n=10), and 55% (n=6) were intubated at the time of LT. Furthermore, most patients required ECMO support (73%, n=8) and 36% (n=4) were on ECMO at the time of LT. Intraoperatively, 64% (n=7) of patients required cardiopulmonary bypass, 73% (n=8) had severe intrathoracic adhesions, 73% (n=8) had delayed chest closure, and 18% (n=2) had an unexpected return to the operating room. Prevalence of primary graft dysfunction grade 2 or 3 at 72 hours was high (91%, n=10), median duration of mechanical ventilation after LT was 10 (6, 19) days, but no one required ECMO rescue. To date, 10 (91%) LTRs have been discharged, and 2 (20%) have been readmitted within 30 days; the median post-LT hospital stay was 18 (14, 24) days; all discharged LTRs required acute rehabilitation for a median of 17.5 (14, 23) days. Ten LTRs (91%) at a median of 208 (167, 245) days post-LT; 1 LTR died 344 days post-LT of treatment-refractory allograft failure due to aspiration and antibody-mediated rejection. Despite pre-LT critical illness, intraoperative challenges, and prolonged post-LT recovery, LT appears feasible for carefully selected patients with irreversible C19 ARDS. [ABSTRACT FROM AUTHOR]