Skin cancers in Italian lung transplant recipients: Incidence and risk factors analysis.

Only a few studies reported the incidence and risk factors of skin cancers in lung transplant recipients. The aim of this study was to determine the cumulative incidence of skin cancers in a cohort of patients undergoing lung transplantation and to define predictors of their development. About 247 consecutive patients receiving lung transplantation at the Thoracic Surgery Unit of University Hospital of Padova between May 1995 and October 2016 were studied. Cumulative incidence of skin cancers was estimated considering death as a competing event. The effect of potential predictors was evaluated with univariate and multivariable Cox models for competing risks. About 37 (15.0%) patients developed skin tumors. The cumulative incidence of any skin cancer was 14.2% at 5 years, 21.4% at 10 years, and 24.3% at 15 years posttransplantation. Age at transplantation, male gender, phototype II, and voriconazole use were independent risk factors for development of squamous cell carcinoma. Only male gender and phototype II were independent risk factors for development of basal cell carcinoma. Since lung transplant recipients have a greater risk of developing skin cancers, the management of these patients needs a multidisciplinary approach, in which dermatologists and transplant physicians have a primary role.

COVID-19 pneumonia in lung transplant recipients: Report of 2 cases.

Coronavirus disease 2019 (COVID-19) has been declared pandemic since March 2020. In Europe, Italy was the first nation affected by this infection. We report anamnestic data, clinical features, and therapeutic management of 2 lung transplant recipients with confirmed COVID-19 pneumonia. Both patients were in good clinical condition before the infection and were receiving immunosuppression with calcineurin inhibitors (CNI), mycophenolate mofetil, and corticosteroids. Whereas mycophenolate mofetil was withdrawn in both cases, CNI were suspended only in the second patient. The first patient always maintained excellent oxygen saturation throughout hospitalization with no need for additional oxygen therapy. He was discharged with a satisfactory pulmonary function and a complete resolution of radiological and clinical findings. However, at discharge SARS-CoV-2 RNA could still be detected in the nasopharyngeal swab and in the stools. The second patient required mechanical ventilation, had a progressive deterioration of his clinical conditions, and had a fatal outcome. Further insight into SARS-CoV-2 infection is eagerly awaited to improve the outcome of transplant recipients affected by COVID-19 pneumonia.

Dyspnea, effort and muscle pain during exercise in lung transplant recipients: an analysis of their association with cardiopulmonary function parameters using machine learning.

BACKGROUND: Despite improvement in lung function, most lung transplant (LTx) recipients show an unexpectedly reduced exercise capacity that could be explained by persisting peripheral muscle dysfunction of multifactorial origin. We analyzed the course of symptoms, including dyspnea, muscle effort and muscle pain and its relation with cardiac and pulmonary function parameters during an incremental exercise testing. METHODS: Twenty-four bilateral LTx recipients were evaluated in an observational cross-sectional study. Recruited patients underwent incremental cardio-pulmonary exercise testing (CPET). Arterial blood gases at rest and peak exercise were measured. Dyspnea, muscle effort and muscle pain were scored according to the Borg modified scale. Potential associations between the severity of symptoms and exercise testing parameters were analyzed using a Forest-Tree Machine Learning approach, which accomplishes for a ratio between number of observations and number of screened variables less than unit. RESULTS: Dyspnea score was significantly associated with maximum power output (WR, watts), and minute ventilation (VE, L/min) at peak exercise. In a controlled subgroup analysis, dyspnea score was a limiting symptom only in LTx recipients who reached the higher levels of WR (≥ 101 watts) and VE (≥ 53 L/min). Muscle effort score was significantly associated with breathing reserve as percent of maximal voluntary ventilation (BR%MVV). The lower the BR%MVV at peak exercise (< 32) the higher the muscle effort perception. Muscle pain score was significantly associated with VO2 peak, arterial [HCO3-] at rest, and VE/VCO2 slope. In a subgroup analysis, muscle pain was the limiting symptom in LTx recipients with a lower VO2 peak (< 15 mL/Kg/min) and a higher VE/VCO2 slope (≥ 32). CONCLUSIONS: The majority of our LTx recipients reported peripheral limitation as the prevalent reason for exercise termination. Muscle pain at peak exercise was strictly associated with basal and exercise-induced metabolic altered pathways. The onset of dyspnea (breathing effort) was associated with the intensity of ventilatory response to meet metabolic demands for increasing WR. Our study suggests that only an accurate assessment of symptoms combined with cardio-pulmonary parameters allows a correct interpretation of exercise limitation and a tailored exercise prescription. The role and mechanisms of muscle pain during exercise in LTx recipients requires further investigations.

The Psychosocial Assessment of Transplant Candidates: Inter-Rater Reliability and Predictive Value of the Italian Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT).

BACKGROUND: The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a comprehensive instrument developed to accurately assess the main pretransplant psychosocial risk factors that may impact transplant outcomes. OBJECTIVE: As neither established assessment procedures nor standardized tools designed to perform pretransplant psychosocial evaluation are currently available in Italy, the present study was designed to develop and preliminarily validate the Italian version of the SIPAT. METHODS: First, our team developed the Italian version of the SIPAT, following standard forward-back translation procedures. Then, the Italian version of the SIPAT was retrospectively and blindly applied to 118 randomly selected transplant cases (40 heart, 40 lung, and 38 liver) by 2 independent examiners. Information about the patients' final transplant listing recommendation (i.e., listing vs. deferral) was independently collected from the respective transplant teams. RESULTS: The inter-rater reliability of the Italian version of the SIPAT scores was substantial (Cohen's kappa = 0.77; P < 0.001). Moreover, the predictive value of the SIPAT ratings on the final transplant listing recommendation (i.e., listing vs. deferral) for each examiner was significant (both P < 0.05). CONCLUSION: Current findings suggest that SIPAT is a promising and reliable instrument in its Italian version. Given these excellent psychometric characteristics, the use of the SIPAT as part of the pretransplant psychosocial evaluation in Italian medical settings is highly encouraged.

Single-center experience in urgent lung transplantation program in a country with a shortage of donors: Does the end justify the means?

In rapidly deteriorating patients awaiting lung transplantation (LT), supportive strategies are only temporary and urgent lung transplant (ULT) remains the last option. The few publications on this topic report conflicting results. According to the Italian national program, patients on mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) may be included in urgent list. We reviewed our experience from January 2012 to December 2014 with ULT and elective lung transplantation (ELT), focusing on outcomes. In the study period, 16 patients received ULT, while 51 received ELT. Among ULT, 1 patient (5.8%) died in waiting list (WL) while 16 patients underwent LT with a median WL time of 6 days. ELT WL mortality was 13.5%, and median WL time 368 days. In-hospital mortality was lower in ELT group (5.8% vs 37.5%, P < .01), while the other postoperative outcomes were not significantly different. For ULT patients, the highest impact risk factors for in-hospital mortality were pretransplant plasma transfusion, recipient Pseudomonas aeruginosa colonization, and high level of reactive C-protein and lactic acid. A ULT program with an accurate recipient selection allows earlier transplantation, reducing WL mortality, with acceptable outcomes, although with a higher in-hospital mortality. Larger studies are needed to validate our results.

Lung Transplantation for Pleuroparenchymal Fibroelastosis: A Single-Center Experience with Revision of Literature.

Pleuroparenchymal fibroelastosis (PPFE) is a rare condition characterized by fibrosis involving the pleura and the upper lobes which can be idiopathic or secondary to chemotherapy, transplantations and occupational exposure. For the end-stage form, lung transplantation (LT) is the treatment of choice. The aim of this study was to report our single-center experience for patients subjected to LT for PPFE and comparing it with the already published evidence on this topic. At our center, we have performed 6 bilateral LTs for patients with PPFE (3 males and 3 females) with a median age of 52 years. Median ICU and in-hospital length of stay were 8 and 30 days, respectively. To date, two patients are alive and four are dead, with a median overall survival of 10 months. In addition, after a formal search using the terms "pleuroparenchymal fibroelastosis AND lung transplantation", we collected 14 studies focused on outcomes after LT. LT for PPFE is technically challenging and its post-operative course could also be complicated. Current available data on LT outcomes are extremely poor and mostly limited to case reports. Further studies need to be published to improve knowledge of this disease and to achieve best outcomes for LT.

Molecular Profiling of Tissue Samples with Chronic Rejection from Patients with Chronic Lung Allograft Dysfunction: A Pilot Study in Cystic Fibrosis Patients.

Chronic rejection (CR) is the main culprit for reduced survival and quality of life in patients undergoing lung transplantation (Ltx). High-throughput approaches have been used to unveil the molecular pathways of CR, mainly in the blood and/or in bronchoalveolar lavage. We hypothesized that a distinct molecular signature characterizes the biopsies of recipients with clinically confirmed histological signs of CR. Eighteen cystic fibrosis patients were included in the study and RNA sequencing was performed in 35 scheduled transbronchial biopsies (TBBs): 5 with acute cellular rejection, 9 with CR, and 13 without any sign of post-LTx complication at the time of biopsy; 8 donor lung samples were used as controls. Three networks with 33, 26, and 36 differentially expressed genes (DEGs) were found in TBBs with CR. Among these, seven genes were common to the identified pathways and possibly linked to CR and five of them (LCN2, CCL11, CX3CL1, CXCL12, MUC4) were confirmed by real-time PCR. Immunohistochemistry was significant for LCN2 and MUC4. This study identified a typical gene expression pattern in TBBs with histological signs of CR and the LCN2 gene appeared to play a central role. Thus, it could be crucial in CR pathophysiology.

Using machine learning to predict antibody response to SARS-CoV-2 vaccination in solid organ transplant recipients: the multicentre ORCHESTRA cohort.

OBJECTIVES: The study aim was to assess predictors of negative antibody response (AbR) in solid organ transplant (SOT) recipients after the first booster of SARS-CoV-2 vaccination. METHODS: Solid organ transplant recipients receiving SARS-CoV-2 vaccination were prospectively enrolled (March 2021-January 2022) at six hospitals in Italy and Spain. AbR was assessed at first dose (t0), second dose (t1), 3 ± 1 month (t2), and 1 month after third dose (t3). Negative AbR at t3 was defined as an anti-receptor binding domain titre <45 BAU/mL. Machine learning models were developed to predict the individual risk of negative (vs. positive) AbR using age, type of transplant, time between transplant and vaccination, immunosuppressive drugs, type of vaccine, and graft function as covariates, subsequently assessed using a validation cohort. RESULTS: Overall, 1615 SOT recipients (1072 [66.3%] males; mean age±standard deviation [SD], 57.85 ± 13.77) were enrolled, and 1211 received three vaccination doses. Negative AbR rate decreased from 93.66% (886/946) to 21.90% (202/923) from t0 to t3. Univariate analysis showed that older patients (mean age, 60.21 ± 11.51 vs. 58.11 ± 13.08), anti-metabolites (57.9% vs. 35.1%), steroids (52.9% vs. 38.5%), recent transplantation (<3 years) (17.8% vs. 2.3%), and kidney, heart, or lung compared with liver transplantation (25%, 31.8%, 30.4% vs. 5.5%) had a higher likelihood of negative AbR. Machine learning (ML) algorithms showing best prediction performance were logistic regression (precision-recall curve-PRAUC mean 0.37 [95%CI 0.36-0.39]) and k-Nearest Neighbours (PRAUC 0.36 [0.35-0.37]). DISCUSSION: Almost a quarter of SOT recipients showed negative AbR after first booster dosage. Unfortunately, clinical information cannot efficiently predict negative AbR even with ML algorithms.

Evaluation of the Kinetics of Antibody Response to COVID-19 Vaccine in Solid Organ Transplant Recipients: The Prospective Multicenter ORCHESTRA Cohort.

Previous studies assessing the antibody response (AbR) to mRNA COVID-19 vaccines in solid organ transplant (SOT) recipients are limited by short follow-up, hampering the analysis of AbR kinetics. We present the ORCHESTRA SOT recipients cohort assessed for AbR at first dose (t0), second dose (t1), and within 3 ± 1 month (t2) after the first dose. We analyzed 1062 SOT patients (kidney, 63.7%; liver, 17.4%; heart, 16.7%; and lung, 2.5%) and 5045 health care workers (HCWs). The AbR rates in the SOTs and HCWs were 52.3% and 99.4%. The antibody levels were significantly higher in the HCWs than in the SOTs (p < 0.001). The kinetics showed an increase (p < 0.001) in antibody levels up to 76 days and a non-significant decrease after 118 days in the SOT recipients versus a decrease up to 76 days (p = 0.02) and a less pronounced decrease between 76 and 118 days (p = 0.04) in the HCWs. Upon multivariable analysis, liver transplant, ≥3 years from SOT, mRNA-1273, azathioprine, and longer time from t0 were associated with a positive AbR at t2. Older age, other comorbidities, mycophenolate, steroids, and impaired graft function were associated with lower AbR probability. Our results may be useful to optimize strategies of immune monitoring after COVID-19 vaccination and indications regarding timing for booster dosages calibrated on SOT patients' characteristics.

Effect of neridronate in osteopenic patients after heart, liver or lung transplant: a multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Transplantation (Tx) is an effective therapeutic option in patients with end-stage organ failure and osteoporosis and related fractures are a recognized complication in these patients. Aim of this study was to evaluate the efficacy of neridronate in patients with reduced bone mass after Tx of the heart, liver or lung. METHODS: In this multicenter randomized double-blind controlled trial (RCT), 22 patients were treated with neridronate (25 mg i.m./month) and 17 received placebo. All patients received daily oral calcium (500 mg) and vitamin D (400 IU). Dual-energy X-ray absorptiometry (DXA) was evaluated at 0, 6 and 12 months and markers of bone turnover at 0, 3, 6, 9 and 12 months. RESULTS: Thirty-nine patients (11 heart Tx, 21 liver Tx, 7 lung Tx), aged 49.3±9.1 years, with a T-score <-2.0 SD at lumbar spine or femoral level were included. In neridronate-treated patients, a significant increase in lumbar bone mineral density (BMD) was observed after 12 months vs. placebo control (0.92±0.13 g/cm2 vs. 0.84±0.08 g/cm2; P=0.005). Femur and hip BMD remained unchanged between groups. Total alkaline phosphatase, bone alkaline phosphatase and beta-cross-laps significantly decreased over the 12 months in neridronate-treated patients vs. placebo, respectively (107.4±74 U/L vs. 157.6±107.1 U/L, P=0.002; 5.7±3.3 µg/L vs. 11.7±4.3 µg/L, P<0.001 and 0.25±0.13 ng/mL vs. 0.73±0.57 ng/mL, P<0.001). No difference was observed between neridronate and placebo groups regarding safety profile. CONCLUSIONS: This is the first RCT that demonstrates the efficacy of neridronate in increasing bone density and reducing bone turnover in organ Tx recipients with significant skeletal morbidity.

Non-invasive ventilation in prone position for refractory hypoxemia after bilateral lung transplantation.

Temporary graft dysfunction with gas exchange abnormalities is a common finding during the postoperative course of a lung transplant and is often determined by the post-reimplantation syndrome. Supportive measures including oxygen by mask, inotropes, diuretics, and pulmonary vasodilators are usually effective in non-severe post-reimplantation syndromes. However, in less-responsive clinical pictures, tracheal intubation with positive pressure ventilation, or non-invasive positive pressure ventilation (NIV), is necessary. We report on the clinical course of two patients suffering from refractory hypoxemia due to post-reimplantation syndrome treated with NIV in the prone and Trendelenburg positions. NIV was well tolerated and led to resolution of atelectactic areas and dishomogeneous lung infiltrates. Repeated turning from supine to prone under non invasive ventilation determined a stable improvement of gas exchange and prevented a more invasive approach. Even though NIV in the prone position has not yet entered into clinical practice, it could be an interesting option to achieve a better match between ventilation and perfusion. This technique, which we successfully applied in lung transplantation, can be easily extended to other lung diseases with non-recruitable dorso-basal areas.

Persistent chylothorax in lymphangioleiomyomatosis treated by intrapleural instillation of povidone.

Lymphangioleiomyomatosis (LAM) is a rare, idiopathic disease affecting young women often complicated by refractory and difficult to manage chylothorax. We report one case of a patient who received a bilateral lung transplantation for LAM presenting a refractory chylothorax. The instillation of povidone iodine in the pleural space was effective in inducing pleurodesis.

Ex-vivo recruitment and x-ray assessment of donor lungs in a challenging retrieval from a donor supported by lvad using the portable normothermic perfusion system: a case report.

BACKGROUND: Lung transplantation (LTx) is limited by the shortage of suitable donors. To overcome this problem, many programs have begun to use donors with extended criteria (marginal donors). However, brain-dead patients with implanted mechanical circulatory support system have rarely been considered as potential lung donors. This case demonstrates the feasibility of lung transplantations from organ donors supported by a mechanical circulatory support system despite the possible difficulties of lung retrieval. CASE PRESENTATION: Our case presents a successful procurement and bilateral lung transplantation from a donor supported by a left ventricular assist device (LVAD) who experienced an intraoperatively haemodynamic complication. The use of portable normothermic perfusion device let us to reduce ischemic injury and assess these marginal donor lungs helping us to determine the clinical suitability for transplantation. Given our extensive experience with the device instrumentation and management, the EVLP process was uneventful with excellent post-transplant course. CONCLUSIONS: This case report demonstrates the feasibility of lung transplantations from organ donors supported by a mechanical circulatory support system using the portable normothermic perfusion platform to assess and preserve these donor lungs.

Asymptomatic Pulmonary Allograft Kaposi Sarcoma: A Case Report.

Solid-organ transplant recipients are at high risk of developing malignancies. A greater risk of Kaposi sarcoma has been reported in lung recipients in our country, particularly in those from Southern Italy, probably due to the high prevalence of Human herpes virus 8 infection. Kaposi sarcoma affecting only the lung allograft is extremely rare. We describe a case of a lung recipient who developed Kaposi sarcoma only in the graft, 22 months after transplant. The patient, a 65-year-old man from Southern Italy, underwent bilateral lung transplant for idiopathic pulmonary fibrosis in January 2009. He developed mild/moderate acute cellular rejection (≥A2) in 4 of 6 scheduled transbronchial biopsies thus was treated with increased immunosuppressive therapy, shifting from cyclosporine to tacrolimus and mycophenolate mofetil. In July 2010, a high-resolution computed tomography scan showed small bilateral lung nodules, despite a generally good condition. After 2 months, his condition worsened with a severe weight loss. A positron emission tomography scan showed mild metabolic activity in the lesions with no other localizations. In October 2010, a lung biopsy was performed, with results showing typical histologic and immunohistochemical features of Kaposi sarcoma. Molecular tissue evaluations and serologic analyses were positive for Human herpes virus 8. The patient's immunosuppressive therapy was suspended, and he started liposomal doxorubicin treatment; however, after the first cycle, he developed severe respiratory dysfunction. The patient died 27 months after lung transplant for neoplasm. Our report highlights the importance of considering Kaposi sarcoma in the differential diagnosis for lung nodules in lung transplant recipients, even in the absence of any initial specific symptom or cutaneous lesion.

Marked alveolar apoptosis/proliferation imbalance in end-stage emphysema.

BACKGROUND: Apoptosis has recently been proposed to contribute to the pathogenesis of emphysema. METHODS: In order to establish if cell fate plays a role even in end-stage disease we studied 16 lungs (9 smoking-associated and 7 alpha1antitrypsin (AAT)-deficiency emphysema) from patients who had undergone lung transplantations. Six unused donor lungs served as controls. Apoptosis was evaluated by TUNEL analysis, single-stranded DNA laddering, electron microscopy and cell proliferation by an immunohistochemical method (MIB1). The role of the transforming growth factor (TGF)-beta1 pathway was also investigated and correlated with epithelial cell turnover and with the severity of inflammatory cell infiltrate. RESULTS: The apoptotic index (AI) was significantly higher in emphysematous lungs compared to the control group (p < or = 0.01), particularly if only lungs with AAT-deficiency emphysema were considered (p < or = 0.01 vs p = 0.09). The proliferation index was similar in patients and controls (1.9 +/- 2.2 vs 1.7 +/- 1.1). An increased number of T lymphocytes was observed in AAT-deficiency lungs than smoking-related cases (p < or = 0.05). TGF-beta1 expression in the alveolar wall was higher in patients with smoking-associated emphysema than in cases with AAT-deficiency emphysema (p < or = 0.05). A positive correlation between TGF-betaRII and AI was observed only in the control group (p < or = 0.005, r2 = 0.8). A negative correlation was found between the TGF-beta pathway (particularly TGF-betaRII) and T lymphocytes infiltrate in smoking-related cases (p < or = 0.05, r2 = 0.99) CONCLUSION: Our findings suggest that apoptosis of alveolar epithelial cells plays an important role even in end-stage emphysema particularly in AAT-deficiency disease. The TGFbeta-1 pathway does not seem to directly influence epithelial turnover in end-stage disease. Inflammatory cytokine different from TGF-beta1 may differently orchestrate cell fate in AAT and smoking-related emphysema types.

Idiopathic interstitial pneumonias: Primum movens: epithelial, endothelial or whatever.

The pathogenesis of idiopathic interstitial pneumonias (IIPs), particularly of idiopathic pulmonary fibrosis (IPF), is still unknown and the precise nature of the primum movens is strongly debated. Epithelial cells can be the first target of various environmental toxic agents. Both types of pneumocytes may be injured. Type I pneumocyte loss, however, is most conspicuous in fibroblastic foci, the principal sites where irreversible fibrogenesis starts. Epithelial regeneration is highly disturbed: cuboidal and bronchial cells are mainly involved in alveolar repair. These cells, unable to accomplish important functions of normal pneumocytes, secrete various factors inducing migration and proliferation of fibroblasts responsible for progressive extracellular matrix accumulation and lung remodelling. Endothelial cells may also be considered the major players in the initiation of fibrogenic events. Microvascular injury has been largely demonstrated as an early event in IPF lungs. Thrombin as well as other coagulation products has many biological effects such as the activation of different profibrotic factors, which in addition to other fibrogenetic molecules released by stimulated endothelium, are responsible for migration and proliferation of fibroblasts. The old pathogenesis of IPF: chronic inflammation can now be considered the principal event in other non IPF-IIPs. Among inflammatory cells, different cell types have been extensively suggested to play a key role in the pathogenesis of pulmonary fibrosis: granulocytes and eosinophils or mast cells. More recently novel mechanisms underlying the pathogenesis of pulmonary fibrosis have been proposed: bone marrow-derived stem cells may play a crucial role in the fibroproliferative response as well as in epithelial regeneration.