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Background: Ex vivo lung perfusion (EVLP) is a relevant procedure to increase the lung donor pool but could potentially increase the airway tree ischemic injury risk., Methods: This study aimed to evaluate the direct effect of EVLP on the airway tree by evaluating bronchial cell vitality and tissue signs of injury on a series of 117 bronchial rings collected from 40 conventional and 19 EVLP-treated lung grafts. Bronchial rings and related scraped bronchial epithelial cells were collected before the EVLP procedure and surgical anastomosis., Results: The preimplantation interval was significantly increased in the EVLP graft group (p < 0.01). Conventional grafts presented cell viability percentages of 47.07 ± 23.41 and 49.65 ± 21.25 in the first and second grafts which did not differ significantly from the EVLP group (first graft 50.54 ± 25.83 and second graft 50.22 ± 20.90 cell viability percentage). No significant differences in terms of histopathological features (edema, inflammatory infiltrate, and mucosa ulceration) were observed comparing conventional and EVLP samples. A comparison of bronchial cell viability and histopathology of EVLP samples retrieved at different time intervals revealed no significant differences. Accordingly, major bronchial complications after lung transplant were not observed in both groups., Conclusions: Based on these data, we observed that EVLP did not significantly impact bronchial cell vitality and airway tissue preservation nor interfere with bronchial anastomosis healing, further supporting it as a safe and useful procedure., (© 2022 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: Lung metabolism during ex vivo lung perfusion (EVLP) is increasingly studied. Microdialysis (MD) allows metabolic monitoring by sampling parenchymal interstitial fluid. This study investigated lung metabolism using MD during EVLP and evaluated whether microdialysate metabolites could improve selection and discriminate outcome of donor lungs., Methods: MD monitoring was used during 14 clinical EVLP procedures. Paired microdialysate and perfusate samples were analyzed for glucose, lactate, pyruvate, glutamate, and the lactate/pyruvate (L/P) ratio, and values that best discriminated an unfavorable outcome were determined. Outcome was defined as unfavorable (lungs not transplanted or transplanted with primary graft dysfunction at 72 hours ≥ 2) or favorable (lungs transplanted with primary graft dysfunction < 2)., Results: Microdialysate markers and the perfusate L/P ratio could discriminate unfavorable outcome with sensitivity and specificity of 0.85 and 0.81 for MD glutamate > 18.4 μmol/liter, 0.81 and 0.74 for MD lactate > 685 μmol/liter, 0.92 and 0.75 for MD glucose > 530 μmol/liter, 0.85 and 0.65 for MD pyruvate > 25 μmol/liter, and 0.73 and 0.67 for perfusate L/P ratio > 24.17. All microdialysate markers, perfusate and microdialysate L/P ratio, and perfusate lactate discriminated outcome when we limited analysis only to transplanted lungs., Conclusions: We report the use of MD to evaluate lung metabolism during clinical EVLP, demonstrating that MD metabolites can contribute to selection of reconditioned lungs and discriminate early outcome after transplantation. Furthermore, glutamate as a marker of lung injury during EVLP is proposed and could hence be used as a potential target for future therapies., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Introduction: Among solid organ recipients lung transplant recipients are at highest risk to be affected by cytomegalovirus infection (CMV) or to die from CMV disease. Two strategies are usually adopted in the clinical management of transplant recipients: antiviral prophylaxis and pre-emptive therapy., Methods: In our center we adopted from 2007 a combined prophylaxis with anti-CMV immunoglobulins in the first post-transplant year and antiviral therapy (gancyclovir or valgancyclovir) from post-transplant day 15 for 3 weeks and in case of CMV bronchoalveolar lavage specimen positivity (polymerase chain reaction or shell vial). Moreover, we studied specific cellular immune response by an Elispot assay to define responder patients by the number of spot forming units (<5 nonresponders, 5-20 weeks, 20-100 good, >100 very good responders)., Results: We reduced acute rejections (from 17% to 6%, odds ratio 3.25), lymphocytic bronchitis bronchiolitis (from 11% to 2%), and first-year CMV pneumonia after the first post-transplant month (from 6.4% to 1%). We showed in nonresponders an earlier onset (68 vs 204 post-transplant days) and a longer duration (>14 days vs <14 days) of infection (P < .05 for all referred data)., Discussion: The morbility reduction has been obtained by antiviral therapy, increasing costs and risk of side effects. Our more recent studies show a population with a good immune response that probably doesn't need a pharmacological intervention but just a strict follow-up., Conclusion: Our proposed strategy is now tailoring the therapy on immune response clinical application, limiting to the specimen positivity in nonresponders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The occurrence and significance of HHV-6 and HHV-7 were investigated in pulmonary tissue from lung transplant recipients. Eighty-seven transbronchial biopsies from 30 patients were studied by quantitative real-time PCR; the association with histopathological features was investigated. HHV-6 and HHV-7-DNA were detected in 6.9% and 9.2% transbronchial biopsies, respectively. A significant association between HHV-6 detection on transbronchial biopsies and interstitial pneumonia was found, in contrast to the lack of association between viral detection on bronchoalveolar lavage and any histopathological feature. No association was evidenced in terms of acute and chronic rejection. The finding of HHV-6 and/or HHV-7-DNA positivity in all the cases with ischemia-reperfusion injury suggests a possible role in favouring ?-herpesviruses reactivation, as previously described for HCMV in renal transplantation.

Lung transplant (LT) recipients among solid organ transplant recipients are at high risk for cytomegalovirus (CMV) infections. We evaluated the effect of CMV-Immunoglobulins (CMV-IG) (Cytotect Biotest) on CMV pneumonia diagnosed in 303 follow-up transbronchial biopsies (TBB) of lung transplant recipients. 24 patients (control group, 155 TBB from 1999 to 2002) received acyclovir for 24 months and 33 recipients (study group, 148 TBB from 2003 to 2008) received a combined CMV prophylaxis consisting of CMV-IG (Cytotect Biotest) for 12 months and a short Ganciclovir or Valganciclovir therapy from 21th to 42th postoperative day followed by acyclovir up to 24 months. In our study the percentage of pneumonia at first month TBB was similar in the study group vs the control group, 9.1% (3/33) vs 8.3% (2/24), p=0.9 ns, but after the first month the percentage was significantly lower in the study group in the first year at follow-up TBB, 1% (1/99) vs 6.4% (5/78), p=0.048, and in first two years follow-up TBB, 0.8% (1/122) vs 6.5% 8/124), p=0.018 (STATISTICAL ANALYSIS: Chi-square test for proportion differences). Our data suggest a strong efficacy of CMV-IG prophylaxis in reducing CMV pneumonia after first month in lung transplant recipients.

Background: Recently, three new polyomaviruses-KI, WU and Merkel cell (MCV)-have been discovered and their detection has been reported in different types of specimens, including respiratory samples, suggesting their shedding in the airways. In lung graft recipients, viral agents are associated with events that may limit the success of transplantation, including organ infection/disease and allograft rejection., Aims: To evaluate the prevalence of KI, WU and MCV in transbronchial biopsies from lung transplant recipients and investigate the association with clinical and histopathological features., Methods: The quantitation of new polyomaviruses DNA by real-time PCR and association with clinical and histopathological findings were evaluated in 66 transbronchial biopsies from lung transplant recipients. Results KI, WU and MCV were detected in 9.2%, 12.3% and 33.8% of specimens, respectively; with mean viral load ranging from 81 copies/10(4) cells for WU to 258 for MCV, thus not differing from that previously reported in native lungs. No significant association with clinical and histopathological findings (including acute respiratory insufficiency, interstitial and organising pneumonia, acute and chronic rejection) was found., Conclusions: Results showed a relatively high frequency of detection of the novel polyomaviruses in transbronchial biopsies from lung transplant recipients. It is likely that this accounted for the positive results found in some cases with different pathological background, although no significant association with a specific clinical and/or histopathological pattern was found.

The monitoring of herpesvirus infection plays a central role in lung transplantation (LT). Herein we evaluated the prevalence of human cytomegalovirus (HCMV), human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), and Epstein-Barr Virus (EBV) DNA in bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB) specimens from LT patients. We associated the findings with the occurrence of interstitial pneumonia, acute rejection, or organizing pneumonia. Viral DNA was detected using real-time polymerase chain reaction (PCR) on 76 paired samples (BAL and TBB) from 27 patients who were receiving a universal combined prophylaxis (cytomegalovirus [CMV] immunoglobulin [Ig] + gancyclovir or valgancyclovir). Histopathological analysis was performed in accordance with the International Society for Heart and Lung Transplantation (ISHLT) criteria. Overall, HCMV results were positive in 25/76 (32.9%) specimens (BAL and/or TBB); HHV-6 in 16 (21.1%); HHV-7 in 40 (52.6%); and EBV in 13 (17.1%). Interstitial pneumonia was diagnosed in 6/76 (7.9%) cases: 5 (83.3%) were positive to HCMV (combined specimens; P < .0001); 5 (83.3%) to HHV-7; and 2 (33.3%) to EBV. An acute rejection episode was diagnosed in 19/76 (25%) cases: 7 (36.8%) were positive to HCMV; 5 (26.3%) to HHV-6; 10 (52.6%) to HHV-7, and 3 (15.8%) to EBV. No significant association was observed between virus detection or load and acute rejection. Organizing pneumonia was diagnosed in 4/76 (5.3%) cases: 1 (25%) positive to HCMV; 4 (100%) to HHV-6 (P < .05); 2 (50%) to HHV-7; and none to EBV. In conclusion, the prevalence of HCMV tended to be lower than that reported in the literature, confirming the importance of universal combined prophylaxis. HCMV was a relevant agent for interstitial pneumonia; although the small numbers limit the statistical analysis, our data did not support an association between herpesviruses and acute rejection episodes, whereas the role of HHV-6 in the pathogenesis of organizing pneumonia deserves further study. Viral detection on TBB could represent an adjunctive tool to complement that on BAL., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Among solid-organ recipients, those with lung transplants are at highest risk of cytomegalovirus (CMV) infection or to die of CMV-associated disease. We evaluated the effect of combined CMV antiviral prophylaxis and CMV-immunoglobulin prophylaxis on CMV-associated pneumonia diagnosed in 303 follow-up transbronchial biopsy (TBB) specimens from lung transplant recipients. At our center, 24 recipients (control group; 1999-2002) received acyclovir for 24 months and 33 recipients (study group; 2003-2008) received combined CMV prophylaxis consisting of CMV immunoglobulin on days 1, 4, 8, 15, and 30 and monthly for 12 months plus gancyclovir or valgancyclovir from postoperative day 21 for 3 weeks followed by acyclovir for up to 24 months. The percentage of pneumonia-positive TBB specimens at 1-month follow-up was similar in the study and control groups: 9.1% (3 of 33 specimens) vs 8.3% (2 of 24) (P = .90). However, after the first month, the percentage of pneumonia-positive TBB specimens was significantly lower in the study group in the first year (months 3, 6, 9, and 12) of follow-up, at 1% (1 of 99) vs 6.4% (5 of 78) (P = .048), and in the first 2 years (months 3, 6, 9, 12, 18, and 24), at 0.8% (1 of 122) vs 6.5% (8 of 124) (P = .02). These data suggest the efficacy of combined prophylaxis to decrease the incidence of CMV-associated pneumonia after the first month in lung transplant recipients. The effect of combined prophylaxis after transplantation seems useful to prevent CMV-associated pneumonia not only in the first year after lung transplantation but also in the second year, which suggests a long-lasting immunologic role of prophylaxis.

Lung transplantation recipients are at high risk for herpesvirus infections. We evaluated the effect of combined cytomegalovirus (CMV) prophylaxis on CMV pneumonia, acute rejection episodes (ARE), lymphocytic bronchitis/bronchiolitis (LB), and obliterans bronchiolitis (OB) diagnosed in 180 transbronchial biopsies (TBB) of lung transplant recipients. At our center, 25 patients (control group; 1999-2002) received acyclovir for 12 months and 21 recipients (study group; 2003-2007) received combined CMV prophylaxis consisting of CMV-IG (Cytotect Biotest) for 12 months and ganciclovir or valganciclovir from postoperative day 21 for 3 weeks. Among the study group (since 2005), CMV shell vial viral culture and Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), and HHV-7 DNA were determined on BAL specimens. In the study group, the number of LB was significantly lower than in the control group (2% vs 11%; P= .04). Similar results were obtained for ARE (6% vs 17%; P= .04). No difference was observed in OB (5% vs 5%; P= .53, NS). A reduction trend was found in CMV pneumonia (2% vs 7%; P= .23, NS). Logistic regression analysis showed a relationship between prophylaxis and a reduced prevalence of ARE (odds ratio [OR] 3.25, confidence interval [CI] 1.12-9.40; P= .03). Finally, in the study group, BAL EBV-DNA positivity and EBV-CMV coinfections were low (6% and 0%, respectively) compared with other herpesviruses and with the literature. Our data suggested the efficacy of combined CMV prophylaxis to prevent ARE and LB, 2 risk factors for chronic rejection, and a possible role to reduce the trend toward CMV pneumonia and EBV infections.

Atypical changes of bronchial respiratory epithelium in a combined heart-lung transplantation recipient are reported. The occurrence of diffuse hyperplasia, squamous metaplasia and dysplasia with foci of disorganized structure of the respiratory epithelium is described. These epithelial changes in the bronchial tree were considered to have arisen after transplantation; their origin, significance and possible evolution are discussed.