Patrick Chevalier

Human Leukocyte Antigen-G Expression After Heart Transplantation Is Associated With a Reduced Incidence of Rejection

Background—Human leukocyte antigen (HLA)-G, a nonclassic major histocompatibility complex class I molecule expressed in the extravillous cytotrophoblast at the feto-maternal interface, is known to protect the fetus from maternal cellular immunity. In a preliminary study, we showed that HLA-G is expressed in the hearts of some patients after heart transplantation. Methods and Results—In the present study, a larger number of patients was investigated to confirm this finding and to look for possible correlations between HLA-G expression and the number and types of rejection. Expression of HLA-G in endomyocardial biopsy specimens was investigated by immunohistochemical analysis, and detection of the soluble HLA-G in the serum was performed by immunoprecipitation followed by Western blot analysis. HLA-G was detected in the biopsy specimens and serum of 9 of 51 patients (18%). The number of episodes of acute rejection was significantly lower in HLA-G-positive patients (1.2±1.1) as compared with HLA-G-negative patients (4.5±2.8) (P <0.001). No chronic rejection was observed in HLA-G-positive patients, whereas 15 HLA-G-negative patients had chronic rejection (P <0.032). A longitudinal study of these patients reveals that the status of HLA-G expression was maintained after 6 months both in serum and in biopsy specimens. During this period, HLA-G-positive patients did not have chronic rejection. Conclusions—There is a significant correlation between rejection and HLA-G expression in the heart after transplantation. HLA-G expression and its effect in reducing the incidence and severity of rejection seem to be stable throughout the evolution.

Combined lung and liver transplantation in patients with cystic fibrosis: A 4 1/2-year experience ☆ ☆☆ ★ ★★ ♢

Patients with cystic fibrosis who have end-stage respiratory failure and associated liver cirrhosis have been considered poor candidates for lung transplantation because of high morbidity and mortality resulting from hepatic insufficiency after the operation. Since April 1989, our policy has been to combine heart-lung or lung and liver transplantation in this group of patients. Between June 1990 and March 1995, among 25 patients accepted in the program for combined transplantation, nine died awaiting transplantation and 10 underwent one of the following procedures: heart-lung-liver transplantation (n = 5), en bloc double lung-liver transplantation (n = 1), sequential double lung-liver transplantation (n = 3), and bilateral lobar lung transplantation from a split left lung and reduced liver transplantation (n = 1). There were 5 male and 5 female patients. The ages of the recipients ranged from 10 to 24 years. Mean forced expiratory volume in 1 second was 29% and mean forced vital capacity was 35% of predicted values. All patients were infected with resistant Pseudomonas, three with Pseudomonas cepaceia, and two patients had Aspergillus species in addition. All patients had severe cirrhosis with portal hypertension. Four patients had a history of esophageal variceal bleeding and two had had previous portosystemic shunts. The operation was performed as a two-stage procedure, the intrathoracic operation being completed before the abdominal stage was begun. Cardiopulmonary bypass was used in all patients because of poor clinical condition. Immunosuppression consisted of azathioprine, cyclosporine, and prednisone, as for isolated lung transplantation. There were two perioperative deaths, one caused by primary liver failure and the second by early lung dysfunction. For the first 3 months after transplantation pulmonary infection was the most common cause of morbidity. Other complications included tracheal stenosis (n = 1), bronchial stenosis (n = 1), biliary stricture (n = 2), and severe ascites (n = 3). All were successfully treated. Obliterative bronchiolitis developed in three patients. This was stabilized with FK 506 in two patients; the other patient underwent retransplantation at 38 months but eventually died of bleeding. Actuarial survival was 70% at 1 year and remained unchanged at 3 years. Significant functional improvement was observed in all survivors. For patients who have chronic respiratory failure with advanced cirrhosis, lung transplantation combined with liver transplantation can be performed with a satisfactory outcome.

Combined heart-lung-liver, double lung-liver, and isolated liver transplantation for cystic fibrosis in children.

Abstract Between June 1990 and September 1995, 8 of 24 children with cystic fibrosis (CF) who were accepted either for combined transplantation or isolated liver transplantation died while waiting for a graft; 11 underwent transplantation and 5 are currently on the waiting list. Of the 11 children who had surgery, 7 (group 1) underwent one of the following procedures: heart‐lung‐liver (n= 4), sequential double lung‐liver (n= 2), or bilateral lobar lung from a split left lung and reduced liver (n= 1). During the same period, the four other children (group 2) underwent isolated liver transplantation (three full‐size livers, one partial liver). There was one perioperative death in each group. Pulmonary infection was the most common cause of morbidity in group 1. Other complications in group 1 included tracheobronchial stenosis (n= 2), biliary stricture (n= 2), and severe ascites (n = 2). All were successfully treated. Oblit‐erative bronchiolitis developed in three patients. This was treated with FK 506. In group 2, pulmonary function tests improved or remained stable after liver transplantation. Surgical complications in group 2 included severe ascites (n= 1), biliary stricture (n= 1), and abscess of the liver (n= 1). Actuarial survival was 85.7 %% 2 % in group 1 at 1 year; it remained unchanged at 3 years and was 64.2 % at 5 years.

Voriconazole pharmacokinetic variability in cystic fibrosis lung transplant patients.

Background. Aspergillosis is a high‐risk complication in cystic fibrosis (CF) lung transplant patients. Azole antifungal drugs inhibit CYP3A4, resulting in significant metabolic drug–drug interactions. Voriconazole (VRZ) was marketed without therapeutic drug monitoring (TDM) recommendations, consistent with favorable pharmacokinetics, but regular determinations of plasma VRZ concentration were introduced in our center to manage interactions with calcineurin inhibitors and to document the achievement of therapeutic levels.

Photosensibilisation au voriconazole : 7 cas

Resume Introduction Le voriconazole est un nouvel antifongique triazole de deuxieme generation derive du fluconazole. Presentant une puissance superieure sur les especes sensibles et un spectre plus large que le fluconazole, il constitue un traitement de choix des aspergilloses pulmonaires invasives et d’autres infections a Fusarium, Scedosporium/Pseudalleschezria et est indique dans les infections invasives a Candida resistantes au fluconazole. Nous rapportons 7 observations de photosensibilisation lors d’un traitement par voriconazole dans un contexte d’immunodepression. Observations Il s’agissait de 5 femmes et 2 hommes âges de 17 a 67 ans (moyenne = 38 ans), recevant un traitement immunosuppresseur dans le cadre d’une transplantation bipulmonaire pour mucoviscidose (5 cas), d’une transplantation renale sur nephroangiosclerose lupique (1 cas) et d’un syndrome de Sjogren (1 cas). Le developpement d’une aspergillose pulmonaire (6 cas) ou d’une infection a Scedosporium (1 cas) a motive la prescription de voriconazole. Une photosensibilisation est apparue dans un delai de 5 semaines a 14 mois apres le debut du traitement, faisant toujours suite a une exposition solaire parfois de faible intensite. Dans tous les cas, l’arret du medicament a entraine rapidement la disparition des signes cutanes. Discussion Les photosensibilisations au voriconazole sont signalees dans la litterature, bien que rarement rapportees. Les malades doivent etre informes de la possibilite de survenue de cet effet indesirable. La prescription de voriconazole en periode d’ensoleillement necessite une protection solaire.

Pharmacological considerations for azole antifungal drug management in cystic fibrosis lung transplant patients

This paper aims to present our experience in the pharmacological approach of the management of azole antifungal drugs in cystic fibrosis lung transplant patients. Cystic fibrosis (CF) lung transplantation is associated with multi-factorial care management, because of immunosuppressive requirements, risk of infections, frequency of gastro-oesophageal reflux disease, hepatic alterations and CF pharmacokinetics (PK) specificities that result in important PK variability. CF is associated with frequent colonization of the airways by filamentous fungi, especially by Aspergillus species. Today the antifungal therapeutic arsenal offers several possibilities for long-term oral therapy including azole drugs (itraconazole, voriconazole and posaconazole). Therefore, nephrotoxic amphotericin B should be avoided. The liver is important in the pharmacological profile of azole drugs, due to metabolic elimination, hepatotoxicity and PK drug-drug interaction (DDI) involving CYP3A4 metabolic inhibition. Targets for such DDI are numerous, but immunosuppressive drugs are of major concern, justifying combined therapeutic drug monitoring (TDM) of both azoles (inhibitors) and immunosuppressants (targets) on an individualized patient basis to adjust the coprescription quantitatively. The risk of long under-dosed periods, frequently addressed in this population, could justify, on a PK basis, the need for combination with an exclusive parenteral antifungal while waiting for azole relevant drug level. High PK variability, the risk of low exposure, therapeutic issues and DDI management in this complex underlying disease justify close monitoring with systematic combined TDM of azole and immunosuppressants, in case of coprescription.

Bridge to transplantation with the DeBakey VAD® axial pump: a single center report

AIMS To report our experience with a left ventricular assist device axial pump as a bridge to transplantation: the DeBakey Ventricular Assist Device (VAD). METHODS From February 1999 to February 2002, nine patients (among which eight males), with a mean age of 47 years, all in NYHA functional class IV, were proposed for a bridge to transplantation with the DeBakey VAD. Five patients had primary dilated cardiomyopathy, four had ischemic cardiomyopathy. All the patients had inotropic support prior to the intervention (dobutamine with a mean dose of 12 mcg/kg per min), six had an intra-aortic counterpulsation, four presented ventricular rhythm disorders. Interventions were performed through sternotomy alone (no need for an abdominal pocket) under extra-corporeal circulation on beating heart (except in one patient suffering from an apical thrombosis for which cardioplegic arrest was performed) as followed: implantation of the apical inflow cannula, tunneling of the percutaneous cable, implantation of the outflow graft under aortic side clamping, starting of the DeBakey VAD during CPB weaning-off. RESULTS Mean support duration was 81+/-62 days (16-224 days). Eight reoperations were required (three for bleeding or cardiac tamponade, one for haemoperitoneum, one for aortic bifurcation thrombectomy, one for right ventricular assist device implantation, two for iterative replacements of the DeBakey VAD). A significant hemolysis was observed in two patients. No device infection or dysfunction were observed. Secondary recovery of a pulsed flow was observed either clinically or by Echo-Doppler in six patients. Five patients were transplanted, four died prior to transplantation (three from multi-organ failure on post-operative day 35, 16 and 50, respectively, and the last patient was found disconnected at day 109). CONCLUSIONS The DeBakey VAD is at the origin of renewed interest for continuous flow assist devices. Still under evaluation, the advantages of miniaturization and facility of implantation of this new device seem to be promising.

Safe Management of Tacrolimus Together With Posaconazole in Lung Transplant Patients With Cystic Fibrosis

Oral posaconazole (PSZ), an azole antifungal drug, was recently introduced for the treatment of invasive fungal infections. The prescription of PSZ together with the immunosuppressant tacrolimus (TRL) was evaluated in 14 lung transplant patients with cystic fibrosis. PSZ inhibited CYP3A4 TRL metabolism, resulting in a decrease of TRL dose by a factor of 3, with tapering to a mean of 2 mg/d. Previous studies with itraconazole and voriconazole showed that TRL dose could be decreased by factors of 5 and 4, respectively. Joint therapeutic drug monitoring of TRL and PSZ was carried out to investigate the high risk of interindividual variability associated with this coprescription in such patients.

Valganciclovir prophylaxis for cytomegalovirus infection in thoracic transplant patients: retrospective study of efficacy, safety, and drug exposure

S. Lefeuvre, P. Chevalier, C. Charpentier, R. Zekkour, L. Havard, M. Benammar, C. Amrein, V. Boussaud, A. Lillo‐Le Louët, R. Guillemain, E.M. Billaud. Valganciclovir prophylaxis for cytomegalovirus infection in thoracic transplant patients: retrospective study of efficacy, safety, and drug exposure.
Transpl Infect Dis 2010: 12: 213–219. All rights reserved

Neuromuscular Painful Disorders: a Rare Side Effect of Voriconazole in Lung Transplant Patients Under Tacrolimus

Voriconazole is an anti-fungal agent active against Aspergillus infection that is used for prophylaxis and curative treatment in lung transplant patients. We present nine cases of painful neuromuscular disorders, an unusual and rare side effect of high-dose voriconazole in association with tacrolimus.