A. Scheed

Immune and Inflammatory Cell Involvement in the Pathology of Idiopathic Pulmonary Arterial Hypertension

RATIONALE Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling. Recent studies have revealed that immune and inflammatory responses play a crucial role in pathogenesis of idiopathic PAH. OBJECTIVES To systematically evaluate the number and cross-sectional distribution of inflammatory cells in different sizes of pulmonary arteries from explanted lungs of patients with idiopathic PAH versus healthy donor lungs and to demonstrate functional relevance by blocking stromal-derived factor-1 by the Spiegelmer NOX-A12 in monocrotaline-induced pulmonary hypertension in rats. METHODS Immunohistochemistry was performed on lung tissue sections from patients with idiopathic PAH and healthy donors. All positively stained cells in whole-lung tissue sections, surrounding the vessels, and in the different compartments of the vessels were counted. To study the effects of blocking SDF-1, rats with monocrotaline-induced pulmonary hypertension were treated with NOX-A12 from Day 21 to Day 35 after monocrotaline administration. MEASUREMENTS AND MAIN RESULTS We found a significant increase of the perivascular number of macrophages (CD68(+)), macrophages/monocytes (CD14(+)), mast cells (toluidine blue(+)), dendritic cells (CD209(+)), T cells (CD3(+)), cytotoxic T cells (CD8(+)), and helper T cells (CD4(+)) in vessels of idiopathic PAH lungs compared with control subjects. FoxP3(+) mononuclear cells were significantly decreased. In the monocrotaline model, the NOX-A12-induced reduction of mast cells, CD68(+) macrophages, and CD3(+) T cells was associated with improvement of hemodynamics and pulmonary vascular remodeling. CONCLUSIONS Our findings reveal altered perivascular inflammatory cell infiltration in pulmonary vascular lesions of patients with idiopathic pulmonary arterial hypertension. Targeting attraction of inflammatory cells by blocking stromal-derived factor-1 may be a novel approach for treatment of PAH.

Clinical ex vivo lung perfusion--pushing the limits.

Ex vivo lung perfusion (EVLP) provides the ability to evaluate donor lungs before transplantation. Yet, limited prospective clinical data exist with regard to its potential to recondition unacceptable donor lungs. This paper summarizes the results of a prospective study of lung transplantation using only initially unacceptable donor lungs, which were improved by EVLP for 2–4 h. From March 2010–June 2011, 13 lungs were evaluated ex vivo. Median donor PaO2 at FiO21.0/PEEP5 was 216 mmHg (range 133–271). Four lungs, all with trauma history, showed no improvement and were discarded. Nine lungs improved to a ΔPO2 higher than 350 mmHg. Median PvO2 at final assessment in these lungs was 466 mmHg (range 434–525). These lungs were transplanted with a median total ischemic time of 577 min (range 486–678). None of the patients developed primary graft dysfunction grades 2 or 3 within 72 h after transplantation. One patient with secondary pulmonary hypertension was left on a planned prolonged extracorporeal membrane oxygenation postoperatively. Median intubation time was 2 days. Thirty‐day mortality was 0%. During the observation period, 119 patients received standard lung transplantation with comparable perioperative outcome. EVLP has a significant potential to improve the quality of otherwise unacceptable donor lungs.

A prospective interventional study on the use of extracorporeal photopheresis in patients with bronchiolitis obliterans syndrome after lung transplantation

BACKGROUND The aim of this prospective study was to evaluate the efficacy and safety of extracorporeal photopheresis (ECP) in patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation and to identify factors predicting treatment response. METHODS The study was performed at a single center and consisted of a cohort of 1,012 lung transplant recipients (November 1989-June 2010). A total of 194 patients developed BOS after a mean of 1,293 ± 1,008 days (range, 99-4,949 days) and received established treatment, and 51 patients received additional ECP. RESULTS Thirty-one (61%) of the ECP-treated patients responded to the therapy and showed sustained stabilization (forced expiratory volume in 1 second range, -5% to 5% vs baseline at start of ECP) of lung function over 6 months. Responders to ECP showed significantly greater survival and less need for retransplantation (p = 0.001) than non-responders. Factors associated with an inferior treatment response were cystic fibrosis as underlying lung disease and a longer time between transplantation and development of BOS. No side effects were observed after ECP. Compared with BOS patients not treated with ECP, the ECP responders showed an improved graft survival (p = 0.05). CONCLUSIONS These results confirm and suggest that early use of ECP could be an effective adjunct treatment for patients who develop BOS after lung transplantation.

Prospective Analysis of Human Cytomegalovirus DNAemia and Specific CD8+ T Cell Responses in Lung Transplant Recipients

In lung transplant recipients (LuTRs), human cytomegalovirus (HCMV) DNAemia may be associated with HCMV disease and reduced survival of the allograft. Because T cells are essential for controlling HCMV replication, we investigated in this prospective study whether the kinetics of plasma HCMV DNA loads in LuTRs are associated with HCMV‐specific CD8+ T cell responses, which were longitudinally assessed using a standardized assay. Sixty‐seven LuTRs were monitored during the first year posttransplantation, with a mean of 17 HCMV DNA PCR quantifications and 11.5 CD8+ T cell tests performed per patient. HCMV‐specific CD8+ T cell responses displayed variable kinetics in different patients, differed significantly before the onset of HCMV DNAemia in LuTRs who subsequently experienced episodes of DNAemia with high (>1000 copies/mL) and low plasma DNA levels (p = 0.0046, Fishers exact test), and were absent before HCMV disease. In HCMV‐seropositive LuTRs, high‐level DNAemia requiring preemptive therapy occurred more frequently when HCMV‐specific CD8+ T cell responses fluctuated, were detected only after HCMV DNA detection, or remained undetectable (p = 0.0392, Fishers exact test). Thus, our data indicate that HCMV‐specific CD8+ T cells influence the magnitude of HCMV DNAemia episodes, and we propose that a standardized measurement of CD8+ T cell immunity might contribute to monitoring the immune status of LuTRs posttransplantation.

Lobar lung transplantation--is it comparable with standard lung transplantation?

Lobar lung transplantation is used mainly for urgent small recipients who are less likely to obtain size matched lungs in due time. Only limited numbers have been published, and we herewith report the largest series of lobar‐LuTX. We analyzed our LuTX database from 1/2001 to 12/2012 and compared the outcome of lobar‐LuTX recipients with those receiving standard LuTX. Seven hundred and seventy‐eighty LuTX (group 1) were performed either in standard technique by implanting the whole lungs (n = 539) or with downsizing by wedge resection of the right middle lobe and/or the left lingula (n = 239). One hundred and thirty‐eight LuTX were performed in lobar technique (group 2) to overcome more pronounced size discrepancies. Patients in group 1 had a different spectrum of diagnoses and were less frequently bridged to LuTX (P < 0.001). Intubation time, ICU stay, and hospital stay were shorter in group 1 (P < 0.001). One‐year survival was 84.8% vs. 65.1%, and 5‐years survival 69.9% vs. 54.9% (P < 0.001). In multivariate analyzes, procedure, diagnosis, and pre‐operative bridging were shown to be significant prognostic factors in survival. Early postoperative outcome in Lobar LuTX was significantly inferior to standard LuTX recipients. However, survival rates of successfully dismissed patients were comparable with standard LuTX (P = 0.168); thereby, Lobar‐LuTX remains an important option in the management of urgent small recipients.

A scale for decision making between whole lung transplantation or lobar transplantation

OBJECTIVE In lung transplantation, appropriate size matching is of crucial importance to achieve satisfactory outcomes. Tailoring of the lung has been repeatedly described as successful means of overcoming size disparities. The goal of this study was to define a parameter helping the surgeon in the decision whether a standard lung transplantation or a lobar transplantation should be anticipated. METHODS We retrospectively analysed the ratio between donor total lung capacity (TLC) and recipient TLC in all lung-transplant procedures performed in our institution from 1 January 2008 to 30 November 2008. The utility of this ratio using predicted recipient TLC (D/pR index) and real recipient TLC (D/rR index) in discriminating between whole lung transplantation and lobar transplantation was studied with the receiver operating characteristic (ROC) analysis. RESULTS The median D/pR index in whole lung transplantations was 1.01 (range: 0.69-1.26) and 1.19 in lobar transplantation (range: 1.09-1.54). In the range between 1.12 and 1.14, sensitivity and specificity are both above 90%. The area under the ROC curve for D/pR index was 0.96. The median D/rR index in whole lung transplantations was 0.95 (range: 0.56-2.74) and 1.58 in lobar transplantation (range: 0.85-2.56). The area under the ROC curve was 0.73. CONCLUSIONS We conclude that the D/pR index is more useful than D/rR index in discriminating between whole lung transplantation and lobar transplantation. With an area under the ROC curve of 0.96, this seems to be a suitable indicator in deciding between whole lung transplantation and lobar transplantation.

Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis

Cystic fibrosis (CF) is an inherited condition that leads to respiratory failure and is the third most common indication for adult bilateral lung transplantation (LuTX). In contrast to other lung diseases, the immune system of CF patients is up‐regulated and we therefore hypothesized that these patients would benefit from induction therapy. In the current study, we investigated the impact of antithymocyte globulin (ATG) induction therapy in CF patients after LuTX. One hundred and forty six patients who underwent LuTX for CF at our centre between January 1999 and December 2010 were included in the study and retrospectively analysed. They were divided into two groups according to the immunosuppressive protocol: group‐A (n = 103) with and group‐B (n = 43) without induction therapy on top of the basic calcineurin inhibitor based triple immunosuppression with mycophenolate mofetil and steroids. Perioperative survival was significantly better in the ATG group, a benefit sustained for the entire follow‐up. ATG induction resulted in a significantly lower incidence of acute rejections without an increase in infectious complications. Taken together, our results indicate that ATG induction therapy confers a significant survival benefit in CF patients undergoing LuTX and reduces rejection. We advocate the use of induction therapy in this patient cohort.

Association of human cytomegalovirus DNAaemia and specific granzyme B responses in lung transplant recipients.

In lung transplant recipients (LTRs), human cytomegalovirus (HCMV) DNAaemia could be associated with HCMV disease and reduced allograft survival. In the present study we analysed whether or not HCMV‐specific granzyme B (Grz‐B) responses indicating CD8+ T cell cytotoxicity exert an impact on HCMV DNAaemia and relate to specific interferon (IFN)‐γ secretion. HCMV‐specific Grz‐B responses were quantitated by enzyme‐linked immunosorbent assay (ELISA) in 70 samples from 39 HCMV seropositive LTRs who were prospectively investigated for HCMV DNA plasma levels and IFN‐γ kinetics using a standardized CD8+ T cell assay (QuantiFERON®‐CMV assay). In all LTRs who were protected from HCMV DNAaemia by early and persistent IFN‐γ responses, Grz‐B responses were also detected. In LTRs who developed episodes of HCMV DNAaemia, the Grz‐B responses which were detected prior to viral DNA detection differed significantly in patients who experienced episodes with high (exceeding 1000 copies/ml) and low plasma DNA levels (P = 0·0290, Fishers exact test). Furthermore, the extent of Grz‐B release prior to viral DNAaemia correlated statistically with the detected levels of IFN‐γ (P < 0·0001, Spearmans rank test). Of note, simultaneous detection of Grz‐B and IFN‐γ secretion was associated significantly with protection from high HCMV DNA plasma levels during the subsequent follow‐up (P = 0·0057, Fishers exact test), and this association was stronger than for IFN‐γ detection alone. We conclude that, in addition to IFN‐γ responses, Grz‐B secretion by CD8+ T cells is essential to control HCMV replication and a simultaneous measurement of IFN‐γ and Grz‐B could contribute to the immune monitoring of LTRs.

Alemtuzumab in Lung Transplantation: An Open‐Label, Randomized, Prospective Single Center Study

Induction therapy with alemtuzumab followed by lower maintenance immunosuppression (IS) has been associated with reduced morbidity and mortality in abdominal and heart transplantation (TX). In the current study, alemtuzumab, in combination with reduced levels of maintenance IS, was compared to thymoglobulin in combination with standard IS. Sixty consecutive patients who underwent lung transplantation (LUTX) at a single center were prospectively randomized in two groups: group A received alemtuzumab in conjunction with reduced doses of tacrolimus, steroids and mycophenolate mofetil. Group B received thymoglobulin in association with standard dose IS. Patient and graft survival, freedom from acute cellular rejection (ACR), lymphocytic bronchiolitis, bronchiolitis obliterans syndrome, kidney function, infectious complications and posttransplant lymphoproliferative disorder were analyzed. Alemtuzumab induction therapy resulted in complete the absence of ACR episodes ≥ A2 within the first year post‐TX. The difference to thymoglobulin was significant (alemtuzumab 0 vs. ATG 0.33; p = 0.019). All other factors studied did not show any differences between the two groups. Alemtuzumab induction therapy after LUTX in combination with reduced maintenance IS significantly reduces higher‐grade rejection rates. This novel therapeutic agent had no impact on survival, infections rates, kidney function and incidence of malignancies.

Considerations on infectious complications using a drowned lung for transplantation

Recently, the applicability of lungs from drowned victims for transplantation has been anecdotically described in literature. However, no data exist about hazards or limitations. Herein, we describe a case of lung transplantation from a submersion victim and the subsequent development of an Aeromonas hydrophila infection in the implanted organ. Based on this case we propose standard procedures, which should be followed when considering drowned donor lungs, in order to minimize risks for infectious complications.