Hemodynamic failure and graft dysfunction after lung transplant: A possible clinical continuum with immediate and long-term consequences.

INTRODUCTION: The postoperative hemodynamic management after lung transplant (LUTX) is guided by limited evidence. We aimed to describe and evaluate risk factors and outcomes of postoperative vasoactive support of LUTX recipients. METHODS: In a single-center retrospective analysis of consecutive adult LUTX, two cohorts were identified: (1) patients needing prolonged vasoactive support (>12 h from ICU admission) (VASO+); (2) or not (VASO-). Postoperative hemodynamic characteristics were thoroughly analyzed. Risk factors and outcomes of VASO+ versus VASO- cohorts were assessed by multivariate logistic regression and propensity score matching. RESULTS: One hundred and thirty-eight patients were included (86 (62%) VASO+ versus 52 (38%) VASO-). Vasopressors (epinephrine, norepinephrine, dopamine) were used in the first postoperative days (vasoactive inotropic score at 12 h: 6 [4-12]), while inodilators (dobutamine, levosimendan) later. Length of vasoactive support was 3 [2-4] days. Independent predictors of vasoactive use were: LUTX indication different from cystic fibrosis (p = .003), higher Oto score (p = .020), longer cold ischemia time (p = .031), but not preoperative cardiac catheterization. VASO+ patients showed concomitant hemodynamic and graft impairment, with longer mechanical ventilation (p = .010), higher primary graft dysfunction (PGD) grade at 72 h (PGD grade > 0 65% vs. 31%, p = .004, OR 4.2 [1.54-11.2]), longer ICU (p < .001) and hospital stay (p = .013). Levosimendan as a second-line inodilator appeared safe. CONCLUSIONS: Vasoactive support is frequently necessary after LUTX, especially in recipients of grafts of lesser quality. Postoperative hemodynamic dysfunction requiring vasopressor support and graft dysfunction may represent a clinical continuum with immediate and long-term consequences. Further studies may elucidate if this represents a possible treatable condition.

Lung Transplantation From Controlled and Uncontrolled Donation After Circulatory Death (DCD) Donors With Long Ischemic Times Managed by Simple Normothermic Ventilation and Ex-Vivo Lung Perfusion Assessment.

Donation after cardiac death (DCD) donors are still subject of studies. In this prospective cohort trial, we compared outcomes after lung transplantation (LT) of subjects receiving lungs from DCD donors with those of subjects receiving lungs from donation after brain death (DBD) donors (ClinicalTrial.gov: NCT02061462). Lungs from DCD donors were preserved in-vivo through normothermic ventilation, as per our protocol. We enrolled candidates for bilateral LT ≥14 years. Candidates for multi-organ or re-LT, donors aged ≥65 years, DCD category I or IV donors were excluded. We recorded clinical data on donors and recipients. Primary endpoint was 30-day mortality. Secondary endpoints were: duration of mechanical ventilation (MV), intensive care unit (ICU) length of stay, severe primary graft dysfunction (PGD3) and chronic lung allograft dysfunction (CLAD). 121 patients (110 DBD Group, 11 DCD Group) were enrolled. 30-day mortality and CLAD prevalence were nil in the DCD Group. DCD Group patients required longer MV (DCD Group: 2 days, DBD Group: 1 day, p = 0.011). ICU length of stay and PGD3 rate were higher in DCD Group but did not significantly differ. LT with DCD grafts procured with our protocols appears safe, despite prolonged ischemia times.

Early pulmonary function and mid-term outcome in lung transplantation after ex-vivo lung perfusion - a single-center, retrospective, observational, cohort study.

Outcomes after transplantation of lungs (LuTX) treated with ex-vivo lung perfusion (EVLP) are debated. In a single-center 8 years of retrospective analysis, we compared: donors' and recipients' characteristics, gas exchange and lung mechanics at ICU admission, 3, 6, and 12 months, and patients' survival of LuTX from standard donors compared with EVLP-treated grafts. A total of 193 LuTX were performed. Thirty-one LuTX, out of 50 EVLP procedures, were carried out: 7 from nonheart beating and 24 from extended criteria brain-dead donors. Recipients' characteristics were similar. At ICU admission, compared with standard donors, EVLP patients had worse PaO2 /FiO2 [276 (206; 374) vs. 204 (133; 245) mmHg, P < 0.05], more frequent extracorporeal support (18% vs. 32%, P = 0.053) and longer mechanical ventilation duration [28 days of ventilator-free days: 27 (24; 28) vs. 26 (19; 27), P < 0.05]. ICU length of stay [4 (2; 9) vs. 6 (3; 12) days, P = 0.208], 28-day survival (99% vs. 97%, P = 0.735), and 1-year respiratory function were similar between groups. Log-rank analysis (median follow-up 2.5 years) demonstrated similar patients' survival (P = 0.439) and time free of chronic lung allograft disease (P = 0.484). The EVLP program increased by 16% the number of LuTX. Compared to standard donors, EVLP patients had worse respiratory function immediately after LuTX but similar early and mid-term outcomes.

COVID-19 in lung transplant recipients: A case series from Milan, Italy.

Limited data are currently available regarding the course of COVID-19 in lung and solid organ transplant recipients. We hereby present four cases of SARS-CoV-2 pneumonia in lung transplant recipients from our center, set in Milan, Italy. We reduced immunosuppressive regimen in all these patients, typically holding the antiproliferative agent and augmenting steroids; everybody received hydroxychloroquine, initial empiric antibiotic treatment with piperacillin/tazobactam, and high-dose low molecular weight heparin. Clinical course seemed favorable in three of our patients, but one of them deteriorated after 10 days of hospitalization, probably due to an acute form of graft dysfunction triggered both by COVID-19 and a nosocomial bacterial infection, and eventually died. Although short-term prognosis could be considered benign in the majority of our patients, we should carefully monitor these individuals in order to detect early sign of clinical deterioration and graft dysfunction in the next few months.

Challenges in the Diagnosis and Management of Bacterial Lung Infections in Solid Organ Recipients: A Narrative Review.

Respiratory infections pose a significant threat to the success of solid organ transplantation, and the diagnosis and management of these infections are challenging. The current narrative review addressed some of these challenges, based on evidence from the literature published in the last 20 years. Specifically, we focused our attention on (i) the obstacles to an etiologic diagnosis of respiratory infections among solid organ transplant recipients, (ii) the management of bacterial respiratory infections in an era characterized by increased antimicrobial resistance, and (iii) the development of antimicrobial stewardship programs dedicated to solid organ transplant recipients.

Quality of Life and Lung Function in Survivors of Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome.

BACKGROUND: Survivors of acute respiratory distress syndrome (ARDS) have long-term impairment of pulmonary function and health-related quality of life, but little is known of outcomes of ARDS survivors treated with extracorporeal membrane oxygenation. The aim of this study was to compare long-term outcomes of ARDS patients treated with or without extracorporeal membrane oxygenation. METHODS: A prospective, observational study of adults with ARDS (January 2013 to December 2015) was conducted at a single center. One year after discharge, survivors underwent pulmonary function tests, computed tomography of the chest, and health-related quality-of-life questionnaires. RESULTS: Eighty-four patients (34 extracorporeal membrane oxygenation, 50 non-extracorporeal membrane oxygenation) were studied; both groups had similar characteristics at baseline, but comorbidity was more common in non-extracorporeal membrane oxygenation (23 of 50 vs. 4 of 34, 46% vs. 12%, P < 0.001), and severity of hypoxemia was greater in extracorporeal membrane oxygenation (median PaO2/FIO2 72 [interquartile range, 50 to 103] vs. 114 [87 to 133] mm Hg, P < 0.001) and respiratory compliance worse. At 1 yr, survival was similar (22/33 vs. 28/47, 66% vs. 59%; P = 0.52), and pulmonary function and computed tomography were almost normal in both groups. Non-extracorporeal membrane oxygenation patients had lower health-related quality-of-life scores and higher rates of posttraumatic stress disorder. CONCLUSIONS: Despite more severe respiratory failure at admission, 1-yr survival of extracorporeal membrane oxygenation patients was not different from that of non-extracorporeal membrane oxygenation patients; each group had almost full recovery of lung function, but non-extracorporeal membrane oxygenation patients had greater impairment of health-related quality of life.

The burden of sinus disease in cystic fibrosis lung transplant recipients.

INTRODUCTION: Sinus disease (SD) in cystic fibrosis (CF) is a known risk factor for disease progression, the upper airways (UAW) being a site of primary colonization with Pseudomonas aeruginosa. UAW may function as reservoir for graft colonization after lung transplantation (LuTx), increasing risk of rejection. Aims of this study were to assess the burden of sinus disease in CF LuTx recipients, considering patient-reported symptoms, endoscopically documented signs and microbiological isolates, comparing colonization between upper and lower airways. METHODS: A prospective, observational study was performed on consecutive CF LuTx recipients, recording history, symptoms, and management of SD. Nasal lavage (NL) was evaluated for UAW colonization, with nasal inspection during bronchoscopy and bronchoalveolar lavage (BAL) used to assess lower airways if clinically indicated. RESULTS: Hundred and fifty-four patients were included. Symptoms of SD were reported in 96 (62%) individuals; 87 (56%) had prior sinus surgery. Only 8 (13%) of 60 individuals undergoing bronchoscopy presented completely normal findings of the nasal cavity. Thirty-six (60%) patients presented the same isolates on both NL and BAL. Polyps and mucosal alterations were significantly less frequently seen endoscopically in patients with normal flora in NL microbiology (respectively, 26% vs 70%, P = .003, and 35% vs 68%, P = .013). CONCLUSIONS: Symptoms of SD affected more than 60% of CF LuTx recipients. Nasal endoscopic inspection identified alterations in 55%. The majority of patients presented the same isolates both on NL and BAL performed on the same visit. These results strongly support a role of paranasal sinuses as "reservoir" for descending re-colonization of the lung graft.

Diagnostic delay in bronchiectasis: an Italian perspective.

It takes ∼3.5 years to reach a diagnosis of bronchiectasis from onset of symptoms: the long patient's journey in Italy https://bit.ly/46XMWAz.

Criteria for clinical stability in hospitalised patients with community-acquired pneumonia.

The American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) suggested two sets of criteria in 2001 and 2007 to define clinical stability in community-acquired pneumonia (CAP). The present study aimed to evaluate the level of agreement between these two sets of criteria and how well they can predict clinical outcomes. A retrospective cohort study was carried out of 487 consecutive patients hospitalised with CAP. Level of agreement was tested using a survival curve analysis, while prediction of outcomes at 30-day follow-up was evaluated through receiver operating characteristic (ROC) analysis. A discrepancy between ATS 2001 and ATS/IDSA 2007 criteria in identifying clinical stability was detected in 62% of the patients. The median (interquartile range) time to clinical stability was 2 (1-4) days based on ATS 2001 and 3 (2-5) days based on ATS/IDSA 2007 criteria (p = 0.012). The daily distribution of patients who reached clinical stability evaluated with both sets was different (p = 0.002). The ROC analysis showed an area under the curve of 0.705 for the ATS 2001 criteria and 0.714 for ATS/IDSA 2007 criteria (p = 0.645). ATS 2001 and ATS/IDSA 2007 criteria for clinical stability in hospitalised patients with CAP are clinically equivalent and both can be used in clinical practice as well as in clinical research.

Idiopathic interstitial pneumonia in a patient with von Hippel-Lindau syndrome: a first case.

Although the mechanisms are not known, this is a case of progressive interstitial lung involvement, with a NSIP radiological pattern, evolving in pulmonary fibrosis in a patient with von Hippel-Lindau syndrome, without extrapulmonary fibrosis. https://bit.ly/3QlNStu.

Bone Disease in Long-Term Lung Transplant Survivors.

BACKGROUND: During the first two years after lung transplantation (LTx), the incidence of fragility fractures (FX) is estimated to be 15-50% and it is lower in patients with cystic fibrosis (CF) as compared with other end-stage lung diseases (nCF). The aim of our study is to compare the skeletal outcomes, after the first 2 years post-LTx, in long-term survivors with CF and nCF. MATERIALS AND METHODS: We evaluated the FX rate, the changes in bone mineral density (BMD) and trabecular bone score (TBS) in 68 patients (38 CF and 30 nCF) who underwent LTx in our center and with a follow-up after LTx longer than 5 years (7.3 ± 2.0 years). RESULTS: After the second year post-LTx: (i) the FX rate was lower than during the first two years post-LTx (4.4 vs. 20.6%, p = 0.004), with no difference between CF and nCF patients (5.3 vs. 3.3%, p = 0.589); (ii) BMD at lumbar spine, femoral neck and total hip remained stable (-1.6 ± 1.0 vs. -1.4 ± 1.1, p = 0.431, -1.8 ± 0.9 vs. -1.9 ± 0.9, p = 0.683, -1.5 ± 0.9 vs. -1.4 ± 0.9, p = 0.678, respectively) as well as TBS (1.200 ± 0.124 vs. 1.199 ± 0.205, p = 0.166). CONCLUSIONS: After the second year post-LTx, the skeletal complications become less frequent and have similar incidence in patients with CF and nCF.

Interventional pulmonology techniques in lung transplantation.

Lung transplantation is a key therapeutic option for several end-stage lung diseases. Interventional pulmonology techniques, mostly bronchoscopy, play a key role throughout the whole path of lung transplantation, from donor evaluation to diagnosis and management of post-transplant complications. We carried out a non-systematic, narrative literature review aimed at describing the main indications, contraindications, performance characteristics and safety profile of interventional pulmonology techniques in the context of lung transplantation. We highlighted the role of bronchoscopy during donor evaluation and described the debated role of surveillance bronchoscopy (with bronchoalveolar lavage and transbronchial biopsy) to detect early rejection, infections and airways complications. The conventional (transbronchial forceps biopsy) and the new techniques (i.e. cryobiopsy, biopsy molecular assessment, probe-based confocal laser endomicroscopy) can detect and grade rejection. Several endoscopic techniques (e.g. balloon dilations, stent placement, ablative techniques) are employed in the management of airways complications (ischemia and necrosis, dehiscence, stenosis and malacia). First line pleural interventions (i.e. thoracentesis, chest tube insertion, indwelling pleural catheters) may be useful in the context of early and late pleural complications occurring after lung transplantation. High quality studies are advocated to define endoscopic standard protocols and thus help improving long-term prognostic outcomes of lung transplant recipients.

Preliminary Evidence of Good Safety Profile and Outcomes of Early Treatment with Tixagevimab/Cilgavimab Compared to Previously Employed Monoclonal Antibodies for COVID-19 in Immunocompromised Patients.

OBJECTIVES: Monoclonal antibodies (mAbs) have proven to be a valuable tool against COVID-19, mostly among subjects with risk factors for progression to severe illness. Tixagevimab/cilgavimab (TIX/CIL), a combination of two Fc-modified human monoclonal antibodies, has been recently approved to be employed as early treatment. METHODS: Two groups of immunocompromised patients exposed to different early treatments (i.e., TIX/CIL vs. other mAbs [casirivimab/imdevimab, bamlanivimab/etesevimab, sotrovimab]) were compared in terms of clinical outcomes (hospitalisation and mortality within 14 days from administration) and time to the negativity of nasal swabs. We used either Pearson's chi-square or Fisher's exact test for categorical variables, whereas the Wilcoxon rank-sum test was employed for continuous ones. Kaplan-Meier curves were produced to compare the time to nasopharyngeal swab negativity. RESULTS: Early treatment with TIX/CIL was administered to 19 immunocompromised patients, while 89 patients received other mAbs. Most of them were solid organ transplant recipients or suffering from hematologic or solid malignancies. Overall, no significant difference was observed between the two groups regarding clinical outcomes. In the TIX/CIL group, one patient (1/19, 5.3%), who was admitted to the emergency room within the first 14 days from treatment and was hospitalised due to COVID-19 progression, died. Regarding the time to nasal swab negativity, no significant difference (p = 0.088) emerged. CONCLUSIONS: Early treatment of SARS-CoV-2 infection with TIX/CIL showed favourable outcomes in a small group of immunocompromised patients, reporting no significant difference compared to similar patients treated with other mAbs.

PD-1 expression in transbronchial biopsies of lung transplant recipients is a possible early predictor of rejection.

Introduction: Chronic lung allograft dysfunction (CLAD) is the main cause of the reduced survival of lung transplanted (LTx) patients. The possible role of immune checkpoint molecules in establishing tolerance has been scarcely investigated in the setting of lung transplantation. Methods: We conducted a retrospective, observational pilot study on a consecutive series of transbronchial cryobiopsies (TCB) obtained from 24 patients during LTx follow-up focusing on PD-1, one of the most investigated immune checkpoint molecules. Results: Results showed that PD-1-expressing T lymphocytes were present in all TCB with a histological diagnosis of acute rejection (AR; 9/9), but not in most (11/15) of the TCB not resulting in a diagnosis of AR (p=0.0006). Notably, the presence of PD-1-expressing T lymphocytes in TCB resulted in a 10-times higher risk of developing chronic lung allograft dysfunction (CLAD), the main cause of the reduced survival of lung transplanted patients, thus being associated with a clearly worst clinical outcome. Discussion: Results of this pilot study indicate a central role of PD-1 in the development of AR and its evolution towards CLAD and suggest that the evaluation of PD-1-expressing lymphocytes in TCB could offer a prognostic advantage in monitoring the onset of AR in patients who underwent lung transplantation.

SARS-CoV-2 antibodies among people with cystic fibrosis prior to the vaccination campaign: A seroprevalence study in two specialized centres in Northern Italy.

The prevalence of anti-SARS-CoV-2 antibodies in people with cystic fibrosis (CF) is largely unknown. We carried out a cross-sectional study between March and June 2021 with the aim of estimating the seroprevalence of anti-SARS-CoV-2 antibodies in two CF centres in Northern Italy. Total serum anti-SARS-CoV-2 (spike) antibodies levels were measured and values ≥0.8 U/mL were considered positive. Among 434 patients aged >12 years, 64 patients had a positive result (14.7%, 95% CI: 11.5-18.4), 36 (56.3%) without experiencing any COVID-19-related symptoms. Three out of 49 transplanted patients tested positive with an odds ratio for a positive result among transplanted as compared to non-transplanted patients of 0.35 (95% CI: 0.07-1.14). No significant differences were observed between sexes, age groups, socioeconomic status and lung disease severity. In conclusion, SARS-CoV-2 has infected a relatively high proportion of our patients but in most cases the infection was asymptomatic.

Longitudinal assessment of renal function after lung transplantation for cystic fibrosis: transition from post-operative acute kidney injury to acute kidney disease and chronic kidney failure.

INTRODUCTION: The clinical trajectory of post-operative acute kidney injury (AKI) following lung transplantation for cystic fibrosis is unknown. METHODS: Incidence and risk factors for post-operative AKI, acute kidney disease (AKD) and chronic kidney disease (CKD) were retrospectively analyzed in cystic fibrosis patients undergoing lung transplantation. Logistic regressions, Chi-square, Cuzick rank tests, and Cox-proportional hazard models were used. RESULTS: Eighty-three patients were included. Creatinine peaked 3[2-4] days after transplantation, with 15(18%), 15(18%), and 20(24%) patients having post-operative AKI stages 1, 2, and 3, while 15(18%), 19(23%) and 10(12%) developed AKD stage 1, stage 2 and 3, respectively. Higher AKI stage was associated with worsening AKD (p = 0.009) and CKD (p = 0.015) stages. Of the 50 patients with AKI, 32(66%) transitioned to AKD stage > 0, and then 27 (56%) to CKD stage > 1. Female sex, extracorporeal membrane oxygenation support as a bridge to lung transplant and at the end of the surgery, the use of intraoperative blood components, and cold-ischemia time were associated with increased risk of post-operative AKI and AKD. Higher AKI stage prolonged invasive mechanical ventilation (p = 0.0001), ICU stay (p = 0.0001), and hospital stay (p = 0.0001), and increased the incidence of primary graft dysfunction (p = 0.035). Both AKI and AKD stages > 2 worsened long-term survival with risk ratios of 3.71 (1.34-10.2), p = 0.0131 and 2.65(1.02-6.87), p = 0.0443, respectively. DISCUSSION: AKI is frequent in cystic fibrosis patients undergoing lung transplantation, it often evolves to AKD and to chronic kidney disease, thereby worsening short- and long-term outcomes.

Lung Biomolecular Profile and Function of Grafts from Donors after Cardiocirculatory Death with Prolonged Donor Warm Ischemia Time.

The acceptable duration of donor warm ischemia time (DWIT) after cardiocirculatory death (DCD) is still debated. We analyzed the biomolecular profile and function during ex vivo lung perfusion (EVLP) of DCD lungs and their correlation with lung transplantation (LuTx) outcomes. Donor data, procurement times, recipient outcomes, and graft function up to 1 year after LuTx were collected. During EVLP, the parameters of graft function and metabolism, perfusate samples to quantify inflammation, glycocalyx breakdown products, coagulation, and endothelial activation markers were obtained. Data were compared to a cohort of extended-criteria donors after brain death (EC-DBD). Eight DBD and seven DCD grafts transplanted after EVLP were analyzed. DCD's DWIT was 201 [188;247] minutes. Donors differed only regarding the duration of mechanical ventilation that was longer in the EC-DBD group. No difference was observed in lung graft function during EVLP. At reperfusion, "wash-out" of inflammatory cells and microthrombi was predominant in DCD grafts. Perfusate biomolecular profile demonstrated marked endothelial activation, characterized by the presence of inflammatory mediators and glycocalyx breakdown products both in DCD and EC-DBD grafts. Early graft function after LuTx was similar between DCD and EC-DBD. DCD lungs exposed to prolonged DWIT represent a potential resource for donation if properly preserved and evaluated.

Safety Profile and Outcomes of Early COVID-19 Treatments in Immunocompromised Patients: A Single-Centre Cohort Study.

BACKGROUND: Early treatment with remdesivir (RMD) or monoclonal antibodies (mAbs) could be a valuable tool in patients at risk of severe COVID-19 with unsatisfactory responses to vaccination. We aim to assess the safety and clinical outcomes of these treatments among immunocompromised subjects. METHODS: We retrospectively reviewed all nonhospitalized patients who received an early treatment with RMD or mAbs for COVID-19, from 25 November 2021 to 25 January 2022, in a large tertiary hospital. Outcomes included frequency of adverse drug reaction (ADR), duration of symptoms and molecular swab positivity, emergency department access, hospital or intensive care unit admission, and mortality in the 14 days following treatment administration. RESULTS: Early treatments were administered to 143 patients, 106/143 (74.1%) immunocompromised, including 41 solid organ and 6 hematopoietic stem cell transplant recipients. Overall, 23/143 (16.1%) subjects reported ADRs. Median time from treatment start to SARS-CoV-2 nasopharyngeal swab negativity and symptom resolution was 10 (IQR 6-16) and 2.5 days (IQR 1.0-6.0), respectively, without differences between immunocompromised and nonimmunocompromised patients. In the 14 days after treatment administration, 5/143 patients (3.5%) were hospitalized and one died as a result of causes related to COVID-19, all of them were immunocompromised. CONCLUSIONS: RMD and mAbs have minimal ADRs and favourable outcomes in immunocompromised patients.

Immune Checkpoints Expression in Chronic Lung Allograft Rejection.

Chronic lung allograft dysfunction (CLAD) is the main cause of poor survival and low quality of life of lung transplanted patients. Several studies have addressed the role of dendritic cells, macrophages, T cells, donor specific as well as anti-HLA antibodies, and interleukins in CLAD, but the expression and function of immune checkpoint molecules has not yet been analyzed, especially in the two CLAD subtypes: BOS (bronchiolitis obliterans syndrome) and RAS (restrictive allograft syndrome). To shed light on this topic, we conducted an observational study on eight consecutive grafts explanted from patients who received lung re-transplantation for CLAD. The expression of a panel of immune molecules (PD1/CD279, PDL1/CD274, CTLA4/CD152, CD4, CD8, hFoxp3, TIGIT, TOX, B-Cell-Specific Activator Protein) was analyzed by immunohistochemistry in these grafts and in six control lungs. Results showed that RAS compared to BOS grafts were characterized by 1) the inversion of the CD4/CD8 ratio; 2) a higher percentage of T lymphocytes expressing the PD-1, PD-L1, and CTLA4 checkpoint molecules; and 3) a significant reduction of exhausted PD-1-expressing T lymphocytes (PD-1pos/TOXpos) and of exhausted Treg (PD-1pos/FOXP3pos) T lymphocytes. Results herein, although being based on a limited number of cases, suggest a role for checkpoint molecules in the development of graft rejection and offer a possible immunological explanation for the worst prognosis of RAS. Our data, which will need to be validated in ampler cohorts of patients, raise the possibility that the evaluation of immune checkpoints during follow-up offers a prognostic advantage in monitoring the onset of rejection, and suggest that the use of compounds that modulate the function of checkpoint molecules could be evaluated in the management of chronic rejection in LTx patients.