Gyoergy Lang

Relationship between Cytomegalovirus DNA Load in Epithelial Lining Fluid and Plasma of Lung Transplant Recipients and Analysis of Coinfection with Epstein-Barr Virus and Human Herpesvirus 6 in the Lung Compartment

ABSTRACT Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in lung transplant recipients (LTRs). The aim of the present study was to elucidate the relationship between the CMV DNA load in the lung compartment and that in plasma. For CMV load determination, the level of CMV DNA in plasma and bronchoalveolar lavage (BAL) samples was measured in a total of 97 paired BAL and plasma samples obtained from 25 LTRs. The original virus concentration in the epithelial lining fluid (ELF) was calculated from the BAL samples by correcting for dilution using the urea dilution method. In addition, the load of Epstein-Barr virus (EBV) and that of human herpesvirus 6 (HHV-6) DNA also were determined in BAL samples, recalculated for their concentrations in the ELF, and compared with the CMV DNA load. CMV DNA was found more frequently and at significantly higher levels in the lung compartment than in plasma (P < 0.001, Wilcoxon test), and the CMV load in the ELF was associated with symptomatic CMV disease. EBV and HHV-6 were detected in 43.6% and 21.7% of the ELF samples, respectively. A statistically significant association was found between the CMV and EBV DNA loads in the ELF (P < 0.001; Spearmans rho = 0.651). Thus, in LTRs, determination of the CMV DNA load in the lung compartment may be advantageous compared to monitoring only viremia. The significant relationship between EBV and CMV DNA loads in the ELF of LTRs and its clinical impact require further investigation.

Pulmonary Retransplantation: Is it Worth the Effort? A Long-term Analysis of 46 Cases

BACKGROUND Pulmonary retransplantation remains the only therapeutic option in some cases of severe primary graft dysfunction (PGD), advanced bronchiolitis obliterans syndrome (BOS), and in some cases of severe airway problems (AWP), mainly cicatriceal stenosis. However, its value has been questioned due to the overall scarcity of donor organs and reports indicating unsatisfactory outcome. We analyzed our institutional experience with pulmonary retransplantation to evaluate its value for different indications. METHODS We retrospectively analyzed all 46 patients undergoing pulmonary retransplantation from the 567 consecutive primary lung or heart-lung transplantations performed in our department from August 1995 to August 2006. We stratified patients according to indication for retransplantation and analyzed the outcome. RESULTS Forty-six patients (mean age 41 +/- 16 years, 18 men and 28 women) underwent pulmonary retransplantation (14 bilateral lung transplantations, 32 single-lung transplantations) for primary graft dysfunction (n = 23), bronchiolitis obliterans syndrome (n = 19) and airway problems (n = 4). Mean time to retransplantation was 26 +/- 27 days in the PGD group, 1,069 +/- 757 days in the BOS group and 220 +/- 321 days in the AWP group. Thirty-day, 1-year and 5-year survival rates after retransplantation were 52.2%, 34.8% and 29.0% in the PGD group and 89.2%, 72.5% and 61.3% in the BOS group, respectively. All 4 patients in the AWP group are presently alive (BOS vs PGD: p = 0.02; BOS vs AWP: p = 0.27; PGD vs AWP: p = 0.06). CONCLUSIONS Pulmonary retransplantation for bronchiolitis obliterans offers long-term survival rates in the range of primary lung transplantation for selected patients. Long-term survival rates for retransplantation due to PGD are significantly lower, warranting restrictive use in this setting. In our experience with a limited number of patients, retransplantation for airway problems has shown excellent results. Pulmonary retransplantation for chronic problems is a plausible approach, provided that patients are carefully selected. Retransplantation for PGD should be avoided.

Standard donor lung procurement with normothermic ex vivo lung perfusion: A prospective randomized clinical trial

BACKGROUND Ex vivo lung perfusion (EVLP) was primarily developed for evaluation of impaired donor lungs. The good clinical results raise the question for its possible impact on lungs meeting standard criteria. Before application of EVLP on such lungs enters routine clinical practice, it must be demonstrated whether EVLP would affect or improve outcome when used in standard donor lungs. We performed a prospective randomized trial to investigate the role of EVLP in standard lung transplantation (Tx). METHODS This prospective randomized clinical trial compared patients who underwent Tx with ex vivo evaluated donor lungs with an equivalent patient population without previous EVLP. RESULTS From October 2013 to May 2015, 193 lung Tx were performed at the Medical University of Vienna. During this period, 80 recipient/donor pairs that met the inclusion criteria were included in this trial, 41 pairs in the control group, and 39 in the EVLP group. In the EVLP group, 4 lungs (10.2%) ultimately did not qualify for Tx and were rejected for lung Tx owing to technical reasons (n = 2) and quality criteria (n = 2). Donor and recipient characteristics were comparable in both groups. Total cold ischemic time in the EVLP group was significantly longer for both implanted lungs (first side, 372 minutes vs 291 minutes, p < 0.001; second side, 437 minutes vs 370 minutes, p = 0.001); median duration of surgery showed no differences (277 minutes vs 275 minutes). Median oxygen partial pressure/fraction of inspired oxygen ratio at 24 hours after Tx was 516 (range, 280-557) in the EVLP group and 491 (range, 352-575) in the control group (p = 0.63). Incidence of primary graft dysfunction >1 was lower in the EVLP group at all time points compared with the control group (24 hours, 5.7% vs 19.5%, p = 0.10), and need for post-operative prolonged extracorporeal membrane oxygenation was lower in the EVLP group (5.7% vs 12.2%, p = 0.44). Short-term clinical outcomes did not differ between recipients in the 2 groups. Patients remained intubated (1.6 days vs 1.6 days, p = 0.67), in the intensive care unit (6 days vs 6 days, p = 0.76), and in the hospital (23 days vs 19 days, p = 0.42) for a comparable period of time. The 30-day survival was 97.1% vs 100% (p = 0.46). CONCLUSIONS This study provides evidence that EVLP can safely be used in standard donor lungs. Functional results and perioperative outcome are comparable to those achieved with standard donor lung preservation techniques. As an evaluation tool, EVLP allows clinicians to identify and to possibly exclude lungs with functional impairment. Finally, EVLP can safely extend total preservation time.

Outcome after extrapleural pneumonectomy for malignant pleural mesothelioma.

BACKGROUND Malignant pleural mesothelioma is a mainly asbestos-related neoplasm that occurs with increasing frequency and is associated with a poor prognosis. Extrapleural pneumonectomy which was initially performed as a stand-alone treatment in patients with resectable disease is now currently almost uniformly applied as part of a multi-modal approach. Its value and advantage over other therapeutic strategies remain points of discussion. We therefore analysed our experience with extrapleural pneumonectomy in the treatment of malignant pleural mesothelioma. METHODS We retrospectively reviewed our institutional experience with all consecutive patients undergoing extrapleural pneumonectomy for malignant pleural mesothelioma from 1994 to 2005. Patients were analysed with regard to hospital mortality and morbidity and long-term outcome. RESULTS Forty-nine patients (10 female/39 male, mean age 58+12 years) underwent extrapleural pneumonectomy during the observation period. Median ICU stay was 1 day, median postoperative length of hospital stay was 13 days. After a mean follow-up of 2573 days, median survival was 376 days (mean 672+121 days, range 9-3384). One-year survival was 53%, 3-year survival 27% and 5-year survival 19%. CONCLUSION Extrapleural pneumonectomy as part of a multi-modality treatment regimen is a good treatment option for selected patients with malignant pleural mesothelioma. The long-term results of this limited series compare favourably to non-surgical treatment regimens. Larger randomised prospective multi-centre trials are warranted to establish clear guidelines.

Awake extracorporeal membrane oxygenation bridging for pulmonary retransplantation provides comparable results to elective retransplantation.

BACKGROUND Lung retransplantation became an accepted treatment for bronchiolitis obliterans syndrome (BOS). However, the value of different bridging modalities for these patients is controversial. METHODS We analyzed outcomes of 39 patients listed for retransplantation between 2008 and 2012. Patients were divided in 3 groups: 23 patients without any bridge modality (elective, Group 1), 11 patients on ventilation and full sedation with or without extracorporeal membrane oxygenation (ECMO) support (sedated bridging, Group 2), and 5 patients awake on ECMO support (awake bridging, Group 3). RESULTS Waiting list mortality was 13% in Group 1, 39% in Group 2, and 0% in Group 3. Perioperative mortality was 20% in Group 1, 29% in Group 2, and 0% in Group 3. Significant differences between Groups 1 and 2 were calculated for time on post-operative ventilation (17.4 vs 27.3 days, p = 0.022), intensive care unit stay (22.0 vs 32.9 days, p = 0.026), and hospital stay (34.7 vs 54.1 days, p = 0.013). However, there were no significant differences between Groups 1 and 3 for post-operative ventilation time (17.4 vs 13.4 days, p = 0.192), for intensive care unit stay (22.0 vs 26.4 days, p = 0.169), or for hospital stay (34.7 vs 34.8 days, p = 0.367). Survival rates at 90 days, 1 year, and 2 years were 80%, 70%, and 53% in Group 1; 71%, 43%, and 29% in Group 2; and 100%, 60%, and 60% in Group 3, respectively. CONCLUSION Awake ECMO bridging for retransplantation provides comparable results to elective retransplantation.

Prolonged venoarterial extracorporeal membrane oxygenation after transplantation restores functional integrity of severely injured lung allografts and prevents the development of pulmonary graft failure in a pig model

OBJECTIVE Prolonged venoarterial extracorporeal membrane oxygenation support during transplantation provides reduction of pulmonary artery flow and allows for protective ventilation. This approach might have the potential to restore function of lungs that would be unsuitable for transplantation. METHODS Left lung transplantation was performed on 16 pigs. Lungs from brain-dead animals were stored for 22 hours at 4 degrees C. Recipients in group A (n = 8) underwent transplantation without cardiopulmonary support followed by ventilation with 10 mL/kg body weight tidal volume. Animals in group B (n = 8) underwent transplantation during venoarterial extracorporeal membrane oxygenation, which was continued for 22 hours, and received low-tidal-volume (5 mL/kg body weight) ventilation. One hour after transplantation, the right lung was excluded. Graft function was compared immediately after exclusion of the contralateral lung (time point 1), 1 hour later (time point 2), and 1 hour after discontinuation of extracorporeal membrane oxygenation (time point 3). RESULTS Four animals in group A did not reach time point 2; all died of pulmonary edema. All animals in group B survived, and at time point 3, the mean Pao(2) value was 323 +/- 129 mm Hg. At time point 2, oxygenation and lung compliance were higher in group B than in group A, whereas pulmonary artery pressure was lower. The same was true when comparing results of group B at time point 3 with results of group A at time point 2. CONCLUSIONS Transplantation during extracorporeal membrane oxygenation with continued use for 24 hours restores function of damaged donor lungs. This could expand the donor pool through wider use of marginal donors.

Treatment of primary graft dysfunction after lung transplantation with orally inhaled AP301: A prospective, randomized pilot study

BACKGROUND Primary graft dysfunction (PGD) after lung transplantation (LTx) carries significant morbidity and mortality in the early post-operative period and is associated with the development of chronic lung allograft dysfunction. AP301, an activator of epithelial sodium channel-mediated Na+ uptake represents a new concept for prevention and treatment of pulmonary edema and has shown promising results in the pre-clinical setting. This pilot study investigated the clinical effect of inhaled AP301 on patients with development of PGD > 1 according to International Society of Heart and Lung Transplantation criteria after primary LTx in a high-volume center and was conducted as a randomized, placebo-controlled, single-center pilot-study including 20 patients. All consecutive patients fulfilling inclusion criteria were screened for PGD at arrival on the intensive care unit (ICU) after LTx. After randomization, inhaled AP301 or placebo was administered by nebulizer twice daily for 7 days or until extubation. Otherwise, patients were treated according to routine clinical protocol. Partial pressure of arterial oxygen (Pao2)/fraction of inspired oxygen (Fio2) values were obtained until extubation and assessed as a primary outcome parameter. Patients were monitored for 30 days within the study protocol. RESULTS From July 2013 to August 2014, 20 patients were randomized 1:1 to AP301 (Group 1) or placebo (Group 2). Both groups were comparable with regard to sex (40% women/60% men vs 50% women/50% men), mean age (55 ± 13 vs 54 ± 6 years), comorbidities, and diagnosis leading to LTx. The Pao2/Fio2 ratio at the time of inclusion was comparable in both groups, with a mean 235.65 ± 90.78 vs 214.2 ± 95.84 (p = 0.405), and there was no significant difference in the extravascular lung water index (13.88 ± 5.28 vs 16 ± 6.29 ml/kg, p = 0.476). The primary end point was mean Pao2/Fio2 ratio values between baseline and Day 3. In the AP301 group, only 1 patient was ventilated at Day 4 and no patients were ventilated after Day 4. In the placebo group, 5 patients were ventilated on Day 4 and 2 patients on Days 5, 6, and 7. The mean increase in the Pao2/Fio2 ratio was significantly higher in Group 1 patients, and the mean between baseline and at 72 hours was 365.6 ± 90.4 in Group 1 vs 335.2 ± 42.3 in Group 2 (p = 0.049). The duration of intubation was shorter in Group 1 than in Group 2 patients (2 ± 0.82 vs 3.7 ± 1.95 days; p = 0.02). ICU stay was 7.5 ± 3.13 days in Group 1 vs 10.8 ± 8.65 days in group 2 (p = 0.57). Survival at 30 days was 100%. No severe adverse events were recorded. CONCLUSIONS This study was designed as a proof-of-concept pilot study. Although it was not powered to achieve statistical significances, the study demonstrated relevant clinical effects of inhaled AP301 on patients with PGD after primary LTx. The improved gas exchange led to a significantly shorter duration of mechanical ventilation and a trend towards a shorter ICU stay. Further investigation of AP301 for treatment of PGD in larger studies is warranted. TRIAL REGISTRATION The trial is registered at https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000716-21/AT.

A rare indication for lung transplantation – pulmonary alveolar microlithiasis: institutional experience of five consecutive cases

Pulmonary alveolar microlithiasis (PAM) is a rare lung disease caused by calcifications within the alveolar space. The only known effective treatment for an end‐stage PAM is lung transplantation (LuTX).

The Lymphatic Phenotype of Lung Allografts in Patients With Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome.

BackgroundChronic lung allograft dysfunction (CLAD), presenting as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) is the major limiting factor of long-term survival in lung transplantation. Its pathogenesis is still obscure. In BOS, persistent alloimmune injury and chronic airway inflammation are suggested. One of the main tasks of the lymphatic vessel (LV) system is the promotion of immune cell trafficking. The formation of new LVs has been shown to trigger chronic allograft rejection in kidney transplants. We therefore sought to address the role of lymphangiogenesis in CLAD. MethodsFormalin-fixed paraffin-embedded tissue samples of 22 patients receiving a lung retransplantation due to BOS or RAS were collected. Lymphatic vessel density (LVD) was determined by immunohistochemical staining for podoplanin. Lung tissue obtained from 13 non-CLAD patients served as control. The impact of LVD on graft survival was assessed. ResultsLymphatic vessel density in CLAD patients did not differ from those in control subjects (median number of LVs per bronchiole: 4.75 (BOS), 6.47 (RAS), 4.25 (control), P = 0.97). Moreover, the number of LVs was not associated with regions of cellular infiltrates (median number of LVs per bronchiole: with infiltrates, 5.00 (BOS), 9.00 (RAS), 4.00 (control), P = 0.62; without infiltrates, 4.5 (BOS), 0.00 (RAS), 4.56 (control), P = 0.74). Lymphatic vessel density did not impact the time to development of BOS or RAS in lung transplantation (low vs high LVD: 38.5 vs 86.0 months, P = 0.15 [BOS]; 60.5 vs 69.5 months, P = 0.80 [RAS]). ConclusionsUnlike chronic organ failure in kidney transplantation, lymphangiogenesis is not altered in CLAD patients. Our findings highlight unique immunological processes leading to BOS and RAS.

Lung transplantation in patients with incidental early stage lung cancer—institutional experience of a high volume center

Incidentally discovered lung cancers in lung transplant (LuTX) recipients are rare but may affect outcome. We aim to report our single center experience with incidence, management, and survival of patients with previously unverified primary lung cancer discovered at the time of LuTX.