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Background: Bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx) results from bronchial epithelial cell (BECs) damages, thought to be orchestrated by T cells primed by antigen-presenting cell presenting alloantigens. In this cell cross-talk, BECs are also suspected to play a pivotal immunosuppressive role in T cell alloreactivity. We studied the immunomodulating role of BECs in a human ex vivo model of allogeneic T cell response, both in healthy subjects and LTx recipients., Methods: BECs from 35 LTx recipients (n = 22 stable, n = 13 BOS) and healthy controls (n = 25) were cultured as primary cell cultures. Their inhibitory capacities through the involvement of tolerogenic molecules (HLA-G, TGF-β, and IL-10) were tested on a mixed lymphocyte reaction between antigen-presenting cells and recipient T cells., Results: Control BECs inhibited T cell alloproliferation by a mean of 53 ± 7%. This inhibitory effect of BECs was significantly reduced in the stable LTx group (24 ± 8%, P = 0.009), but not in the BOS TxP group (53 ± 10%, P = 0.97). Neutralization of HLA-G, TGF-β, and IL-10 partially restored T cell alloproliferation, arguing for their involvement in the immunosuppressive effect of BECs. BECs culture supernatant from stable LTx patients with impaired BEC properties showed a skewed Th2-type secretion profile (high IL-4/IFN-γ ratio)., Conclusions: The inhibitory properties of BECs are dysregulated in stable LTx recipients, which could suggest their instrumental role in the initiation of BOS process and potential targeted therapies.

Background: New methods of solid-phase assays, such as Luminex assay, with high sensitivity in detecting anti-human leukocyte antigen (HLA) antibodies (Abs), have increased the proportion of sensitized candidates waiting for lung transplantation (LTx). However, how to apply these results clinically during graft allocation is debated: strict exclusion of candidates with Luminex-positive results can lead to lost opportunities for Tx. We retrospectively analyzed the clinical impact of pre-LTx Luminex-detected Abs on post-LTx outcomes for patients who underwent LTx before the availability of Luminex assay., Methods: We analyzed data for 56 successive patients who underwent LTx before 2008 and were considered to not have anti-HLA Abs by then-available methods of detection at the date of their LTx. Pre-LTx sera from these patients were retested by Luminex assay. Using log-rank test, freedom from bronchiolitis obliterans syndrome (BOS) and graft survival were compared between patients with and without pre-LTx Luminex-detected anti-HLA Abs classes I and II and donor-specific Abs (DSA) classes I and II., Results: Freedom from bronchiolitis obliterans syndrome was lower, and mortality was higher for patients with than those without pre-LTx Luminex-detected DSA class II (P=0.004 and P=0.007, respectively) but did not differ for patients with and without DSA class I or anti-HLA Abs class I or II., Conclusions: It suggests to avoid attributing graft with forbidden antigens to sensitized candidates with Luminex-detected DSA class II and to evaluate the role of specific posttransplantation protocols for LTx candidates who require emergency LTx.

Background: The continuing significant number of patients who die while on a waiting list for lung transplantation (LTx) has led several countries to modify their lung allocation rules in recent years. France has implemented high-emergency allocation rules to allow patients at imminent risk of death to undergo priority transplantation within several days. The aim of this study was to report on the early (2-year) experience of high-emergency LTx (HELTx) in France., Methods: From July 1, 2007, to June 30, 2008, 186 patients underwent LTx in France in nine centers. Among them, 32 patients (17.2%) underwent HELTx (19 with cystic fibrosis, 7 pulmonary fibrosis, and 6 other diagnoses). The reasons for HELTx were risk of invasive mechanical ventilation (n=20), invasive mechanical ventilation (n=8), and extracorporeal membrane oxygenation (n=4)., Results: The median time between being placed on the HELTx waiting list and LTx was 3 days (interquartile range: 1-8 days). Survival rates in the HELTx group were 90.5%, 71%, 64.5%, 55%, and 51.5% at 1, 3, 6, 12, and 24 months, respectively, which were significantly lower than for 154 patients who underwent regular, nonurgent LTx during the study period (88.5%, 83%, 79%, 77%, and 71%, respectively)., Conclusions: Our data demonstrate that the new LTx allocation rules implemented in France since 2007 allow for rapid organ procurement for patients at imminent high risk of death. HELTx is feasible but yields poorer survival than elective LTx. Further studies are needed to assess implications of this organ allocation policy on the long run.

Background: Exercise training is established as adjuvant therapy for chronic heart failure, but the prognostic value of improvement in exercise capacity after exercise training has never been evaluated., Methods and Results: In this prospective bicentric study, all chronic heart failure patients with left ventricular ejection fraction <45% who underwent an exercise training program in a cardiac rehabilitation center between January 2004 and September 2006 were consecutively included. Improvement in exercise capacity was assessed by change in peak oxygen consumption (deltaPVo(2)) and in PVo(2) expressed as a percentage of predicted PVo(2) (delta%PPVo(2)) measured before and after the training program. We included 155 patients (54+/-12 years old, male 81%, left ventricular ejection fraction=29.5+/-7.1%). Patients underwent 20 (10-30) training sessions. PVo(2) and %PPVo(2) were significantly increased after the training program (14% and 13%, respectively, P<0.001 for both). After 16+/-6 months follow-up, 27 patients had a cardiac event (death [n=12], cardiac transplantation [n=5], hospitalization for acute heart failure [n=10]). Univariate analysis revealed that among 17 significant predictors of cardiac events, the 2 more powerful ones were level of B-type natriuretic peptide at baseline (P<0.0001) and improvement in exercise capacity as assessed by deltaPVo(2) and delta%PPVo(2) (P<0.0001). Multivariate analysis revealed B-type natriuretic peptide level and delta%PPVo(2) as only independent predictive factors of outcome (P=0.01). The risk ratio of cardiac events for nonresponse versus response to the training program (defined as median delta%PPVo(2)<6%) was 8.2 (P=0.0006)., Conclusions: Among patients with chronic heart failure, the lack of improvement in exercise capacity after an exercise training program has strong prognostic value for adverse cardiac events independent of classical predictive factors such as left ventricular ejection fraction, New York Heart Association class, and B-type natriuretic peptide level.

Large intra-individual variability in plasma levels may limit the interest of therapeutic drug monitoring based on a single determination. Indinavir concentrations were determined both in plasma and hair samples, and correlated with concomitant plasma HIV-RNA in 43 HIV-infected patients. In multivariate analysis, significant association was found between HIV-RNA below 50 copies/ml and indinavir concentrations in hair but not in plasma, suggesting that hair concentrations gave more extensive information on drug exposure than a single plasma sample.

Background: Lung transplantation (LT) may represent a therapeutic option in case of advanced pulmonary Langerhans' cell histiocytosis (PLCH). Little is known however about the characteristics of the patients considered for LT or its results., Methods: We conducted a retrospective multicenter study by questionnaire on 39 patients who underwent LT for end-stage PLCH at seven centers in France., Results: Of the 39 patients, 15 received single lung transplantation, 15 double lung transplantation and 9 heart-lung transplantation. At evaluation, extrapulmonary involvement was present in 31% of the patients, pulmonary hypertension (PAPm>25 mm Hg) was observed in 92% of cases and was moderate-to-severe (PAPm> or =35 mm Hg) in 72.5%. The survival was 76.9% at 1 year, 63.6% at 2 years, 57.2% at 5 years, and 53.7% at 10 years. Recurrence of the disease occurred in eight cases (20.5%) with no impact on the survival rate. The sole risk factor for recurrence of the disease was the presence of preoperative extrapulmonary involvement., Conclusion: Severe pulmonary hypertension is a common feature in patients with end-stage PLCH. Given the good postransplant survival rate and despite a recurrence rate of the disease of approximately 20% after LT, we conclude that LT is a therapeutic option in this setting.

Background: Although the possibility of reversing hepatopulmonary syndrome (HPS) after liver transplantation is now well established, the proportion of patients in whom reversibility is observed and the time to resolution of HPS remain uncertain., Methods: We analyzed the outcome of all adult patients with HPS who underwent orthotopic liver transplantation in all the liver transplant centers in Paris, during a 10-year period., Results: Twenty-three adult patients (median age, 47 years; range, 14-64) underwent transplantation in four institutions. Median PaO(2) was 52 (range, 32-67) mm Hg and median alveolar-arterial oxygen gradient was 66 mm Hg. When patients were breathing 100% O(2), median PaO(2) was 310 (range, 74-663) mm Hg. Median isotopic shunt ratio was 33% (range, 0-80%). The overall mortality during the study period was 30.5% (7/23). Perioperative mortality was 8.5%, whereas late mortality was 22%. None of the preoperative characteristics of HPS (isotopic shunt ratio, PaO(2) on room air or on 100% oxygen) was associated with overall postoperative mortality. Of the 21 patients surviving the perioperative period (median follow-up, 17 months; range, 0.5-72), a decrease in alveolar-arterial oxygen gradient of at least 5 mm Hg and at least 10 mm Hg was observed in 21 of 21 and in 18 of 21 patients, respectively, with great variations in the time of improvement. The threshold of 70 mm Hg was reached in 15 patients. The lower the preoperative PaO(2), the longer the time to reach this point., Conclusion: Our data strongly support the role of orthotopic liver transplantation in adult patients with HPS, regardless of its severity.

Background: The preventive effect of inhaled nitric oxide (NO) and pentoxifylline (PTX) administered during reperfusion has been demonstrated on experimental models of lung ischemia/reperfusion (I/R) injury but this strategy is not validated in clinical lung transplantation. The aim of this study was to assess retrospectively the protective effect of inhaled NO and PTX after lung transplantation., Methods: Twenty-three consecutive patients who received inhaled NO (10 ppm) and PTX (NO-PTX group) at the time of reperfusion were compared retrospectively with (1) 23 consecutive patients transplanted just before the use of NO-PTX (control group 23); (2) 95 patients representing all the patients of the series who did not receive NO-PTX (control group 95), with respect to I/R injury related complications. In particular, the incidence of pulmonary reimplantation edema and early hemodynamic failure, the PaO2/FIO2 ratio as well as the duration of mechanical ventilation and the 2-month mortality rates were compared., Results: Reimplantation edema was observed in 6/23 patients (26%) in the NO-PTX group vs. 13/23 patients (56%) in the control group 23 (P=0.035) and 48/95 patients (50%) in the control group 95 (P=0.035). The worst PaO2/FIO2 ratio during the first three postoperative days was 240-102 mmHg in the NO-PTX group vs. 162+/-88 mmHg (P=0.01) and 176+/-107 mmHg (P=0.01) in the control group 23 and the control group 95, respectively. The duration of mechanical ventilation was 2.1+/-2.4 days in the NO-PTX group vs. 7+/-9 days in the control group 23 (P=0.02) and 6+/-7 days in the control group 95 (P=0.01). The 2-month mortality rate was 4.3% in the NO-PTX group vs. 26% (P=0.04) and 21% (P=0.07) in the control group 23 and the control group 95, respectively., Conclusions: The marked decrease in the incidence of allograft dysfunction compared with two historical control groups suggests that PTX and inhaled NO given before and throughout reperfusion are protective against I/R injury in the setting of clinical transplantation.