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Introduction: Pediatric lung transplantations (LTx) remains a small part of LTx performed worldwide. The majority of these Tx concerns young adolescents, transplantations in infants being anecdotic. We conducted a retrospective study of LTx in children and adolescents in one center in Paris from the beginning of the 90's to 2013., Methods: Data from Broussais then HEGP were collected retrospectively from 1990 to 2013: 380 LTx were reported in 368 patients including 111 LTx performed among children from 5 to 18 years of age (30%)., Results: One hundred and eleven patients received 121 LTx: 86 bilateral LTx, 13 combined lung-liver, 3 monopulmonary, 5 heart-lung and 4 combined heart-lung-liver Tx. Eighty-eight percent of the patients had cystic fibrosis. Median age was 14 years, weight 34 kg and height 144 cm. Median age of donors was 27 years, weight 60 kg and height 167 cm. Conditional survival for children was not different than adults: 72% at one year, 42% at 5 years, 37% at 10 years and 26% at 15 years. There was not overall early mortality after transplantation. Era graft survival was significantly higher after year 2000 (53% at 5 years vs 32% P=0.03)., Conclusion: Lung transplantation among children under 18 years have similar outcome to those of adult patients., (Copyright © 2014. Published by Elsevier Masson SAS.)

Background: Humoral immune responses during heart transplantation may result in antibody-mediated rejection (AMR), which is now taken into account on endomyocardial biopsy (EMB) specimens and ranked according to the pathologic AMR (pAMR) grades of the International Society for Heart and Lung Transplantation classification. This classification might benefit from new immunohistological markers and validation by others biomarkers, namely donor-specific antibodies (DSA)., Methods: From the 293 protocol EMBs performed in 113 patients in our institution during a 1-year period for this prospective study, 280 EMB specimens were available with both histology and immunohistochemistry. C4d and labeling of intravascular cells by cluster of differentiation (CD) 68 were performed on paraffin sections. Available sera (n = 150) concomitant of EMB specimens were tested for the presence of DSA. All of the pAMR+ EMB specimens, along with a set of randomized pAMR0 EMB specimens, were immunolabeled for mammalian target of rapamycin (mTOR) effectors, phosphorylated 70 S6-kinase (p70S6K) and phosphorylated S6 ribosomal protein (pS6RP)., Results: AMR was diagnosed in 37 EMB specimens (13.2%): 1 pAMR1(I+), 27 pAMR1(H+), and 9 pAMR2. The proportion of DSA-positive EMB varied according to the pAMR grade, with pAMR0, pAMR1(H+), and pAMR2 EMB presenting 17.6%, 77.3%, and 100% of DSA-positivity, respectively. Among the 30 pAMR+ specimens with available DSA testing and the 30 pAMR0 randomized specimens, mTOR pathway immunohistochemistry showed endothelial cell positivity for p70S6K in 17 pAMR+ EMB specimens (56.7%) and in 1 pAMR0 EMB specimen (3.3%). pS6RP was detected in 8 pAMR+ EMB specimens (26.7%) and in 1 pAMR0 EMB specimen (3.3%)., Conclusions: p70S6K and pS6RP immunohistochemistry afford new markers of AMR on EMB specimens because their expression is correlated with microcirculation inflammation and DSA. The correlation of DSA with pAMR grade suggests that this grading system is valid., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Therapeutic drug monitoring of ciclosporin has been recognized as an essential tool in the management of allograft transplant recipients, as it could help improve their outcome. However, there is still no consensus about the optimal method for monitoring ciclosporin after thoracic transplantation. Better knowledge of the pharmacokinetics of ciclosporin in thoracic transplant patients and design of tools dedicated to ciclosporin monitoring could help its practice and its outcome in this population of patients. The aims of this study were to (i) investigate the population pharmacokinetics of ciclosporin in thoracic (heart or lung) transplant patients and study the influence of a range of potential covariates, including demographic, clinical and genetic factors, on pharmacokinetic parameters; and (ii) develop a Bayesian estimator able to predict the individual pharmacokinetic parameters and exposures indices in this population of patients., Methods: The analysis was performed with 187 full pharmacokinetic profiles obtained in 57 lung and 19 heart transplant patients within the first year post-transplantation. A population pharmacokinetic model was developed by non-linear mixed-effects modelling using NONMEM(®) (version 7.1) from an index dataset (118 profiles). On the basis of this population model and a limited number of blood samples, a Bayesian estimator able to determine ciclosporin area under the blood concentration-time curve (AUC) during a dosage interval was built and evaluated in the validation dataset (69 profiles)., Results: Ciclosporin pharmacokinetics were described using a two-compartment model with time-lagged first order absorption and first-order elimination. The final population model included sex as a covariate: ciclosporin apparent oral clearance was on average 37 % faster in male than in female patients (34.8 vs. 25.4 L/h, p < 0.001). Good predictive performance of the Bayesian estimator was obtained using three blood concentrations measured at 40 min, 2 h and 4 h post-dose, with a non-significant bias of -5 % between the estimated and the reference trapezoidal AUC and a good precision (relative mean square error = 13 %)., Conclusion: Ciclosporin population pharmacokinetic analysis in thoracic transplant patients (including patients with cystic fibrosis) showed a significant influence of sex on apparent clearance. The Bayesian estimator developed in this study yielded accurate prediction of ciclosporin exposure in this population throughout the first year post-transplantation. This tool may allow routine ciclosporin dose individualization.

The objective of this pharmacodynamic study was to longitudinally assess the activity of calcineurin during the first 2 years after lung transplantation. From March 2004 to October 2008, 107 patients were prospectively enrolled and their follow-up was performed until 2009. Calcineurin activity was measured in peripheral blood mononuclear cells. We report that calcineurin activity was linked to both acute and chronic rejection. An optimal activity for calcineurin with two thresholds was defined, and we found that the risk of rejection was higher when the enzyme activity was above the upper threshold of 102 pmol/mg/min or below the lower threshold of 12 pmol/mg/min. In addition, we report that the occurrence of malignancies and viral infections was significantly higher in patients displaying very low levels of calcineurin activity. Taken together, these findings suggest that the measurement of calcineurin activity may provide useful information for the management of the prevention therapy of patients receiving lung transplantation.

In heart transplants, the significance of very late rejection (after 7 years post-transplant, VLR) detected by routine endomyocardial biopsies (EMB) remains uncertain. Here, we assessed the prevalence, histopathological and immunological phenotype, and outcome of VLR in clinically stable patients. Between 1985 and 2009, 10 662 protocol EMB were performed at our institution in 398 consecutive heart transplants recipients. Among the 196 patients with >7-year follow-up, 20 (10.2%) presented subclinical ≥3A/2R-ISHLT rejection. The VLR group was compared to a matched control group of patients without rejection. All biopsies were stained for C4d/C3d/CD68 with sera screened for the presence of donor-specific antibodies (DSAs). In addition to cellular infiltrates with myocyte damage, 60% of VLR patients had evidence of intravascular macrophages. C4d and/or C3d-capillary deposition was found in 55% VLR EMB. All cases of VLR associated with microcirculation injury had DSAs (mean DSA(max) -MFI = 1751 ± 583). This entity was absent from the control group (p < 0.0001). Finally, after a similar follow-up postreference EMB of 6.4 ± 1 years, the mean of CAV grade was 0.76 ± 0.18 in the control group compared to 2.06 ± 0.26 in the VLR group respectively, p = 0.001). There was no difference in patient survival between study and control groups. In conclusion, VLR is frequently associated with complement-cascade activation, microvascular injury and DSA, suggesting an antibody-mediated process. VLR is associated with a dramatic progression to severe CAV in long-term follow-up., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The objective of this study was to retrospectively analyze risk factors associated with post-transplant lymphoproliferative disease (PTLD) in a cohort of 112 lung transplant recipients with cystic fibrosis (CF). Prior to transplantation, patients were tested for Epstein-Barr virus (EBV), human herpesvirus (HHV types 1, 2, 3, 6, and 8), herpes zoster virus, and cytomegalovirus (CMV) serologies. PTLD diagnosis was established based on increased EBV viral charge plus clinical/radiographic findings and confirmed by biopsy. Negative EBV and HHV serologies at the time of lung transplantation (LTx) were significant risk factors associated with development of PTLD in patients with CF in the univariate logistic regression analysis (p < 0.05) and also in the multivariate analysis (odds ratio of 77.5 and 12.5, respectively). CMV serology, CMV mismatch, acute rejection in the first three months following LTx, HLA-A3 antigen expression, and female gender did not affect PTLD. Our study confirmed the presence of a strong association between negative EBV serology at the time of LTx and PTLD and suggested an independent effect of negative HHV serology on PTLD., (© 2011 John Wiley & Sons A/S.)

Pulmonary resection after lung transplantation in end-stage cystic fibrosis presents unique challenges, and scant literature exists to guide physicians. We retrospectively reviewed 78 transplants for cystic fibrosis performed between 2003 and 2008. Fourteen patients underwent posttransplantation pulmonary resection. We analyzed the indications, surgical procedures, outcomes, and survival. Three pneumonectomies, 4 lobectomies, and 11 wedge resections were carried out. We identified 2 groups based on indication: a diagnostic group, and a therapeutic group of patients in whom the indications were septic native lung in 2, allograft infection in 2, lobar torsion in 2, pulmonary infarction in 2, and size mismatch in 4. The mean intensive care unit and hospital stays were 29 and 50 days, respectively. Four (28.57%) patients died during follow-up, including 2 who underwent pneumonectomy; 10 (71.43%) are still alive. Survival was 43.43 ± 8.06 months, and it was not significantly different from that in cystic fibrosis patients who had lung transplantation without pulmonary resection. Pulmonary resection following lung transplantation in cystic fibrosis patients showed acceptable survival and surgical risk, but metachronous pneumonectomy was associated with higher mortality.

Purpose: Voriconazole is widely used to treat invasive aspergillosis after lung transplantation. In cystic fibrosis patients, the interindividual variability in drug disposition complicates the optimal voriconazole dosing and increases the risk of toxicity. The objective of this retrospective study was to evaluate the influence of CYP2C19 genotype on voriconazole response in lung transplant patients with cystic fibrosis., Methods: We retrospectively studied 24 Caucasian cystic fibrosis lung transplant recipients who received voriconazole. We analyzed the influence of CYP2C19 genotype (*2 and *17 alleles) on voriconazole exposure and maintenance dose and side effects., Results: Heterozygous carriers of the CYP2C19*2-deficient allele required lower maintenance doses (440 ± 107 mg/day) compared with wild-type and CYP2C19*17-allele carriers (633 ± 197 mg/day and 600 ± 193 mg/day, respectively, P<0.05). The time to achieve the therapeutic range and the proportion of out-of-range concentrations were significantly higher in the CYP2C19*2 group (31.3% vs. 12.1% and 9.8% of above-range levels in the CYP2C19*1 and CYP2C19*17 groups, respectively) or CYP2C19*17 group (37.9% vs. 15.6% and 13% of below-range levels in the CYP2C19*1 and CYP2C19*2 groups, respectively) (P<0.01). No relationship was found between voriconazole toxicity and CYP2C19 status., Conclusions: In this frail population, voriconazole exposure is strongly influenced by CYP2C19 genotype, and determining the genotype before voriconazole initiation may help determine the initial dosing regimen that will promptly achieve therapeutic plasma levels without producing out-of-range levels.

Tacrolimus (TRL) is an immunosuppressive drug characterized by a narrow therapeutic index, low bioavailability, and pharmacokinetic variability. Intravenous (i.v.) TRL may be needed whenever the oral route is unavailable. The small amount of infusion formulation (5 mg/mL) results in a large dilution and need for careful technical management of the infusion. This study addressed the feasibility to provide sublingual (SL) as an alternative to i.v.. TRL for transplanted patients. In a substudy, we performed a retrospective analysis of 17 lung and heart transplant patients using SL TRL. It included therapeutic drug monitoring and 4 area under curve (AUC) measurements. Patients received SL TRL on a dose-to-dose basis from the oral formulation. The mean age of the subjects (14 male, 3 female) was 35.3 ± 15.6 years; 146 trough (C(0)) samples were collected during the SL period (15.8 ± 20.6 days) showing a conformity level of 90.4%. Mean dose, C(0), and AUC of SL tacrolimus were 0.116 ± 0.096 mg/kg, 12.9 ± 5 ng/mL, and 230 ± 74 ng·h/mL, respectively, with an average 1 hour time to peak concentration. Acute rejection episodes, renal toxicity, and drug interactions were not observed. This study supported the convenience of short-term SL TRL administration, even in unconscious patients. Further investigations are needed to validate the dose range of the SL route., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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.

Oral ganciclovir (GCV) was replaced by prodrug valganciclovir (vGCV) for cytomegalovirus (CMV) prophylaxis. We assessed retrospectively (2005-2007) vGCV effectiveness and safety during prophylaxis and 4 months after, in heart (HTx) and lung transplantation (LTx), including lung transplant for cystic fibrosis (CFTx). Patients with stable renal function received vGCV 900 mg daily during 3-6 and 8-12 months in HTx and LTx. Effectiveness was assessed by antigenemia (pp65Ag) and a GCV therapeutic drug monitoring to document exposure. A total of 32 patients (11 HTx, 7 LTx, and 14 CFTx) received vGCV for 106+/-67 days in HTx versus 270+/-85 days in LTx and CFTx. Doses were 700+/-225, 915+/-60, and 820+/-150 mg/24 h in HTx, LTx, and CFTx showing acceptable mean trough GCV 0.75+/-0.5 mg/L. Two of 9 cases of neutropenia were attributable to vGCV. Three CMV donor-positive/recipient-negative CFTx patients presented positive pp65Ag; 2 developed CMV disease (6%). We found that vGCV 900 mg, adapted to renal function, was effective and safe for long CMV prophylaxis together with efficient exposure in thoracic transplantation.

Background: Ventricular assistance device (VAD) implantation provides large ventricular core biopsies available for pathological assessment. We present here the pathological data from 60 apex removed during a 7-year-period in a single institution., Results: The most frequent specific lesions were ischemic myocardial damage. Nonspecific pathological features were quite as frequently observed and correspond either to dilated cardiomyopathies, chronic ischemic cardiopathies, or miscellaneous conditions. Myocarditis represented 10 out of the 60 cases. The pathological data changed the clinical diagnosis in four cases: 1 case of juvenile hemochromatosis featuring as myocarditis and three cases of myocarditis featuring as dilated cardiomyopathies., Conclusion: Apex pathological analysis provides definite diagnosis and contributes to determine the cases which the cardiac disease have a possibility to recover under VAD.

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., Methods: VRZ TDM data analysis for trough concentration (C0) and peak concentration (C2) was carried out, using validated liquid chromatography assay with ultraviolet detection, for 35 CF lung transplant patients (mean age 25 years, mean weight 47 kg, balanced sex ratio) since 2003. Therapeutic range (C0: 1.5 +/- 0.5 - C2 : 4.0 +/- 1.0 mg/L) was expressed relative to pivotal pharmacokinetic trial data., Results: The duration of VRZ treatment ranged from 9 days to 22 months. The recommended standard dose of VRZ (200 mg twice a day, following the loading dose) resulted in significant plasma concentrations (>0.5 mg/L) in 20% of CF lung transplant patients. Therapeutic concentrations were obtained using higher doses (average 570 +/- 160 mg/day, +43%, P<0.01). Despite adaptation, C0 remained <0.5 mg/L (11%), even when the drug was administered intravenously, highlighting the variability of VRZ pharmacokinetics, possibly enhanced by CYP2C19 polymorphism. The risk of inefficacy during periods of underdosage was overcome by treatment with antifungal drug combinations (caspofungin, n=10). The therapeutic index was limited by neurologic effects (14%) and hepatic abnormalities (30%). VRZ concentrations correlated significantly (P<0.01) with aspartate aminotransferase levels but not with bilirubin levels. VRZ acted as a metabolic inhibitor of tacrolimus (C0 to dose ratio 5.8 +/- 2.6, n=31/VRZ versus 1.7 +/- 0.9 alone, P<0.001). Large changes in azole concentration affected the magnitude of the drug-drug interactions and adjustment requirements., Conclusions: TDM is required because VRZ levels are often undetectable in treated CF lung transplant patients, supporting the use of antifungal drug combinations until achievement of VRZ C0 at a steady state between 1 and 2 mg/L. Plasma VRZ concentrations should be determined for the quantitative, individualized management of drug-drug interactions in lung transplant patients, in particular immunosuppressant such as tacrolimus, considering VRZ to be both a target and an inhibitor of CYP3A4.

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.

Three patients with end-stage cystic fibrosis (CF) underwent single lung transplantation (SLT) with contralateral pneumonectomy. In the first case, contralateral pneumonectomy (CP) was performed before SLT. The patient is alive with no signs of infection or rejection. For the other 2 cases, CP was performed after SLT. One patient died 8 months later with septicemia; the other patient died after 10 days because of complicated bronchopleural fistula and infection of the pneumonectomy space. SLT can be a good option for some patients with CF. The outcome is good when CP is done before SLT. However, CP must be done simultaneously with SLTX.

We have analyzed the evolution of renal status beyond the perioperative period in patients with cystic fibrosis (CF) undergoing lung transplantation and presented histological analysis of 15 patients biopsied for an episode of accelerated renal function loss (RFL). Episodes of accelerated RFL after the perioperative period occurred in 32.5% of patients and significantly raised the risk of end-stage renal disease (ESRD) (p < 0.001). The histologic lesions associated with these episodes differed according to the time of onset. Early onset (10 cases) was associated with tubulointerstitial lesions in the form of oxalate nephropathy (50%) and/or a pigmented tubulopathy (80%). This latter was correlated with treatment with antiviral agents (p = 0.002) and aminoside and glycopeptide antibiotics (p = 0.03) administered in the month preceding biopsy. Lesions in late episodes of accelerated RFL (5 cases) were principally vascular: arteriosclerosis and arteriolosclerosis (p = 0.007, p = 0.00002), correlated with diabetic glomerulosclerosis or focal segmental glomerulosclerosis in the absence of prominent diabetic changes. Specific calcineurin-inhibitor nephrotoxicity was present in 93.3% of biopsies associated with thrombotic microangiopathy in 46.7% of cases. The identification of specific etiologies of progressive kidney disease in patients with CF after lung transplantation should permit more effective post-transplant care of these patients.

Objective: Cardiac stem cell transplantation as a potential means of regenerating infarcted myocardium is currently receiving a great deal of interest. However, data on these endogenous cardiac precursors are primarily derived from animal studies, and their clinical relevance still remains elusive., Methods: We prospectively screened 32 endomyocardial biopsies harvested from heart transplant recipients (off rejection episodes) and 18 right appendage biopsies collected during coronary artery bypass surgery, and processed the tissue specimens for the immunohistochemical detection of markers of stemness (c-kit, MDR-1, Isl-1), hematopoietic origin (CD45), mast cells (tryptase), endothelial cells (CD105), and cardiac lineage (Nkx2.5). Confocal microscopy was used for colocalization experiments. Three right appendage biopsies were also cultured for 2 to 3 weeks, at the completion of which c-kit-positive cells were sorted by flow cytometry., Results: In endomyocardial biopsies, a median number of 2.7 (1.8-4) c-kit-positive cells/mm(2) were found, and this number was even significantly smaller in right appendage biopsies (1 [0.5-1.8] c-kit-positive cell/mm(2), P = .01). All of these c-kit-positive cells co-stained for CD45 and were more specifically identified as mast cells by their positive staining for the specific tryptase marker. However, none of the c-kit-positive cells expressed the markers of stemness MDR-1 and Isl-1 or colocalized with CD105. Flow cytometry confirmed the small number of c-kit-positive cells in cultured right atrial appendages., Conclusion: These data raise a cautionary note on the therapeutic exploitation of cardiac stem cells in patients with ischemic cardiomyopathy, who may be the elective candidates for regenerative therapy.

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.

We report a case of unilateral pulmonary edema due to the decompensation of an asymptomatic ipsilateral pulmonary venous stenosis by a contralateral pulmonary embolism. Emergency surgery included pulmonary embolectomy and refashioning of the stenotic pulmonary venous anastomosis.

Acute renal insufficiency (ARI) is a frequent complication of nonrenal solid organ transplantation and may be responsible for an unfavorable outcome, particularly if dialysis is required. The etiology of post-transplantation ARI is poorly understood, with only isolated clinical cases being reported, most imputed to drug toxicity. We report here, the first three observations of irreversible ARI associated with acute oxalate nephropathy (AON) in the course of nonrenal organ transplants: a lung transplant and a lung-liver transplant in two patients with mucoviscidosis, and a cardiac transplant. The diagnosis of AON was made histologically. In all three cases, the ARI supervened after prolonged consumption of antibiotics capable of interfering with the colonic flora, and leading to enteric hyperoxaluria. The recognition of AON as a cause of post-transplantation, ARI underlines hyperoxaluria and digestive hyperabsorption of oxalate as specific risk factors for AON and should permit better posttransplant care of these patients.

Background: Voriconazole is a new second-generation fluconazole-derived triazole. With greater potency against susceptible species and a broader spectrum of activity than fluconazole, it is the treatment of choice for invasive pulmonary aspergillosis and other fungal infections (Fusarium, Scedosporium/Pseudalleschezria) is indicated in a visit Candida infections refractory to fluconazole. We describe 7 cases of photosensitivity during treatment with voriconazole in a setting of immunodepression., Case Reports: The patients comprised 5 women and 2 men with a mean age of 38 years (17-67 years). Five had undergone pulmonary transplantation for mucoviscidosis, one had undergone kidney transplantation for lupus nephroangiosclerosis and one was on long-term systemic steroid treatment for Sjögren's syndrome. All patients had very severe immunosuppression and were receiving voriconazole for pulmonary aspergillosis (6 cases) or Scedosporium infection (1 case). Photosensitization appeared within 5 weeks to 14 months after the start of treatment, and in all cases followed exposure to sun, occasionally at low levels. In all cases, cutaneous lesions rapidly disappeared on discontinuation of treatment., Discussion: There have been reports in the literature, although rare, of photosensitivity with voriconazole. Patients must be informed of the possibility of this adverse effect and sun protection must be recommended when voriconazole is prescribed, particularly during periods of intensive exposure.

Background: Previous reports, all concerning pulsatile devices, have indicated an increased risk of development of circulating antileukocyte antigen (HLA; human leukocyte antigen) antibodies during ventricular assist device (VAD) support. We investigated sensitization in patients implanted with the DeBakey VAD (MicroMed Technology, Inc, Houston, TX) axial flow pump as a bridge to heart transplantation., Methods: Inclusion criteria for this prospective study were the following. Patients implanted with the DeBakey VAD axial flow pump, without HLA antibodies prior to implantation, with a duration of support of at least one month. The HLA antibody testing for IgG and IgM class I and II antibodies was performed weekly during support, using both a complement dependant cytotoxicity assay and an enzyme-linked immunosorbent assay (ELISA). Retrospective cross match was performed for all patients transplanted. The occurrence of graft rejection was determined by regular endomyocardial biopsies after heart transplantation, graded according to the International Society for Heart and Lung Transplantation (ISHLT) guidelines. Additionally, the transfusion history was reviewed for all patients., Results: Fourteen patients were included representing 1,220 cumulative patient-days of support (mean duration time on support, 87 days). No patient developed detectable IgG antibodies to class I or II. One patient had a positive ELISA, corresponding to nonsignificant (6/30) class I IgM antibodies at 3 weeks postimplantation. Ten patients underwent successful heart transplantation, representing 156 cumulative months. No retrospective cross match was positive. The percentage of significant acute rejection episodes (ISHLT grade 3A or more) was 6% and 4.3% in the first 6 months and from 6 to 12 months, respectively. No vascular rejection was noted. The posttransplantation survival rate was 87% at 6 months and 75% at 1 year, respectively., Conclusions: Patients implanted with the DeBakey VAD axial flow pump as a bridge to heart transplantation do not appear to be exposed to an increased risk of sensitization.

A 37-year-old female patient had a cardiac transplantation for dilated cardiomyopathy. She was sensitized by two pregnancies showing anti-human leukocyte antigen I and II antibodies. The pretransplantation crossmatch was negative, but she developed acute humoral rejection characterized by vascular C4d deposits, arteriolitis, and intravascular leukocyte accumulation and adhesion in venules. Although C4d deposits disappeared in 4 weeks, she had persistent endothelial cell activation (endothelial expression of ELAM-1, VCAM-1, or human leukocyte antigen class II) throughout the 6 months of follow-up. Although she received intensive immunosuppression, she presented three episodes of acute cellular rejection during that period of time. This case shows that C4d deposits represent a sensitive marker of acute humoral rejection in cardiac transplantation. Therefore, C4d immunofluorescence should be more frequently assessed in endomyocardial biopsies.

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.

Objective: To assess the incidence and etiology of colonization and infection of pulmonary artery catheters inserted in cardiac surgery patients. To determine the influence of some variables on the risk of developing pulmonary artery catheter colonization and infection., Design: Prospective observational study of pulmonary artery catheters inserted into the internal jugular vein that were in place for >48 hrs over a 13-month period. Data collected included age, gender, nature of the cardiac surgery intervention, duration of extracorporeal circulation, date of insertion and removal, subsequent infection, and curative antimicrobial therapy. End points were pulmonary artery catheter colonization with >or=10(3) colonies on quantitative cultures and pulmonary artery catheter-related bacteremia. Risk factors for colonization were determined by multiple logistic regression., Setting: A 17-bed cardiac surgery intensive care unit in a 480-bed teaching hospital in Paris., Patients: Patients undergoing cardiac surgery procedures between May 1, 1997, and May 31, 1998., Interventions: None., Measurements and Main Results: Of 164 pulmonary artery catheters inserted in 157 patients, 19 (11.6%) and 1 (0.6%) were associated with colonization (mean duration of catheterization, 7.5 +/- 2.8 days) and bacteremia, respectively. These data represent an incidence of 17.7 and 0.93 episodes per 1000 catheterization-days, respectively. Pulmonary artery catheter colonization was caused by Gram-positive cocci in 48% (67% were coagulase-negative staphylococci), Gram-negative rods in 48%, and Candida albicans in 4%. From multivariate analysis, >4 days of catheterization was the single variable associated with a significantly increased risk of pulmonary artery catheter colonization (odds ratio, 9.81; 95% confidence interval, 1.24-77.5, p = .03)., Conclusions: Our data show that the risk of pulmonary artery catheter-related colonization and bacteremia is quite low despite the use of a high-risk insertion site. In cardiac surgery patient populations, a trial evaluating the impact of a systematic pulmonary artery catheter removal after 4 days is warranted.

Toxoplasmosis is a life-threatening disease in heart- or lung transplant recipients that can result either from the reactivation of a latent infection or from an organ-transmitted infection. The diagnosis of acute toxoplasmosis is easy in cases of seroconversion following a mismatch. However, when the recipient is Toxoplasma-seropositive before transplantation, usual serological techniques do not allow the differentiation between endogenous and organ-related reinfection. The aim of this study was to determine whether western blotting could contribute to this differentiation. Sequential sera from two heart- and one liver- and lung transplant patients whose anti-Toxoplasma antibody titers strongly increased after transplantation, were analyzed by western blotting. Neosynthesized IgG were observed on blots incubated with the sera from two patients who had received transplants from Toxoplasma-seropositive donors, whereas no neosynthesized IgG was detected on blots from the patient who had received a transplant from a Toxoplasma-seronegative donor. Our results suggest that the detection of neosynthesized IgG in the recipient may be related to the recognition of a new parasite strain possibly brought by the transplant from a Toxoplasma-seropositive donor.

With a survival rate of 70% at 3 years, cardiac transplantation is the best treatment for end-stage heart disease. However, progressive development of graft atherosclerosis is frequent. Diagnosis of transplant coronary disease remains difficult and non-invasive tests have proved relatively insensitive. Therefore, coronary angiography performed annually is still the gold-standard test for the detection of heart transplant vasculopathy. We analyzed the records of 96 patients (82 men and 14 women) who were transplanted from 1986 to 1996. Mean age was 53 +/- 2.7 and time elapsed from transplantation was mean 5.3 +/- 10 years. All patients had rest myocardial TI 201 perfusion SPECT, followed by MIBI gated SPECT after exercise. MIBI gated SPECT allows simultaneous evaluation of perfusion, regional LV function and global ejection fraction. Angiocoronarography, performed in all patients during the six months following radionuclide investigation, showed the presence of coronary heart vasculopathy in nine (9.3%). Seven of these patients had abnormal dual isotope imaging and 2 of them had normal perfusion but altered LV regional function. Sensitivity of dual isotope scintigraphy was 77% and specificity was 97.7%. Dual isotope scintigraphy is helpful to detect coronary vasculopathy in heart transplant recipients and may reduce indications of angiocoronarography.

Exhaled nitric oxide is considered as a marker of airway inflammation. We report here our preliminary experience with single-breath exhaled nitric oxide measured in lung transplant patients with and without bronchiolitis obliterans syndrome and in cardiac transplant patients. Peak and end-expiratory nitric oxide concentrations did not differ between groups, but single-breath exhaled nitric oxide recordings were strikingly different in patients suffering from bronchiolitis obliterans syndrome, with a slower decrease from peak to end-expiratory nitric oxide concentration. Further studies are required in order to determine whether theses abnormalities reflect the inflammatory process of bronchiolitis obliterans syndrome.

Eleven days after double lung transplantation for cystic fibrosis, an 18-year-old patient developed a disseminated Fusarium solani infection with tricuspid valve endocarditis. This infection occurred under fluconazole and immunosuppressive therapy with cyclosporin, prednisone and azathioprine, with a normal leucocyte count. Liposomal amphotericin B allowed blood culture negativation. The patient died from a bacterial septic shock.

Cystic fibrosis is a recessive disease that causes changes in mucus secretions, affecting different systems: respiratory, digestive, pancreatic, hepatic; resulting in obstructions and secondary infections. Transplantation may be used for the most severe forms and is then complicated by the pediatric context, the existence of malabsorption and secondary infections and the type of transplantation (pulmonary and/or hepatic). The follow-up is characterized by pulmonary infections and pulmonary chronic rejection. In our experience, the initiation of the immunosuppressive treatment must avoid corticoids in the early post-transplantation days and have recourse to intravenous cyclosporin (CyA) 2 mg/kg/day, given on average for one month in an oral form. In case of persistent acute rejection, tacrolimus (FK 506) is instituted. Oral CyA (10-12 mg/kg/day) seems more sensitive to malabsorption syndrome than FK 506 (0.2 mg/kg/day). In both cases, the development of an inhibitory metabolic interaction in the presence of itraconazole must be taken into account: used against aspergillosis, itraconazole is metabolized as CyA and FK 506 by Cyt P450 3A4. The intensity of the interaction is twofold for CyA versus fivefold for FK 506. The strategy for the use of other recently available immunosuppressives such as mycophenolate is under evaluation.

In the past twenty years, the increased number of organ transplant recipients and better immunosuppressive regims have enhanced transplant survival, and several transplant recipients may conceive pregnancy or paternity after the graft. There is no French registry of posttransplant pregnancies, but analysis of the international literature reports 2300 pregnancies after kidney transplantation, 100 pregnancies after heart and 3 after heart-lung transplantation, 90 pregnancies after liver transplantation. Paternity after the graft may occur with no increased incidence of malformations, nor teratogenic and immunosuppressive effects due to the therapeutic regimen. All pregnancies after transplantation have to be considered at high risk, underlying the need for simultaneous follow-up by the gyneco-obstetrical team for the baby and the pregnancy and by the transplant team for the graft and the mother. Outcome is generally excellent for the mother and the baby. However, transplant recipients with either high blood pressure, diabetes, serum creatinine above 160 mumol/l or within less than 1 year after the graft should be considered at too high risk to conceive a pregnancy with no deleterious effect on the mother and/or on the foetus.

Background: The knowledge of long-term changes in the transplanted heart is still incomplete. Among these changes that could potentially have an adverse effect on long-term cardiac function, myocardial fibrosis is of great concern. The aim of this study was to investigate the possible influence of acute or chronic rejection on the development of myocardial fibrosis in cardiac allografts., Methods: We used light microscopic computer-assisted morphometry of collagen density in 200 right ventricular endomyocardial biopsy specimens taken routinely in 21 heart transplant recipients during a mean follow-up period of 36 months (range, 12 to 84). The 21 patients were divided into two groups according to the presence of chronic rejection assessed by coronary angiography. The first group consisted of 11 patients with no chronic rejection; the second group consisted of 10 patients with chronic rejection. Both groups were divided into four subgroups according to the highest grade of acute rejection reached during the follow-up period (subgroup 1, no acute rejection or grade 1A; subgroup 2, grade 1B; subgroup 3, grades 3A or 3B; subgroup 4, grade 4). Patients of both groups were selected on the basis of similarity patterns in clinical characteristics and mean follow-up time., Results: Patients with no chronic rejection had relatively little variation in serial determinations of myocardial collagen density. During the prechronic and chronic phases in patients with chronic rejection, we found no overall increase in myocardial collagen density. In both the chronic rejection and no chronic rejection groups there was no consistent relationship between myocardial collagen density and severity of acute rejection. In both groups there were occasional strikingly elevated myocardial collagen density values that were well above the other serial determinations. These elevated values of collagen density were mainly a result of scars, the sequellae of prior myocyte damage, because neither interstitial nor perivascular fibrosis could be detected., Conclusion: During this long-term follow-up study of endomyocardial biopsy samples, we found no significant association between either acute or chronic rejection and the later increase in myocardial collagen density.

Background and Methods: We investigated extracorporeal photochemotherapy--which consists of the collection of blood mononuclear cells by means of a cell separator, their exposure to ultraviolet A light in the presence of a photoactivatable molecule such as 8-methoxypsoralen, and their intravenous reinjection into the patient--for the treatment of an acute lung rejection episode in a severely infected patient, assuming that its mechanism of action is an immunomodulation rather than an actual immunosuppression., Results: Three weeks after the simultaneous beginning of antiinfectious and extracorporeal photochemotherapy treatments, the patient improved clinically. Acute lung rejection was no longer detectable histologically 4 weeks after the beginning of extracorporeal photochemotherapy. Twenty-two months after the beginning of extracorporeal photochemotherapy (47 months after transplantation), the patient was living a normal life., Conclusions: We believe this treatment may be considered for further studies not only in acute lung rejection therapy when intensive immunosuppression is contraindicated but also as a means of rejection prevention.

Objective: Treatment of transplant rejection with muromonab CD3 (Orthoclone OKT3) may result in haemodynamic instability and pulmonary oedema, which would question its prophylactic use. The aim of this study was to the evaluate haemodynamic and respiratory tolerance of prophylactic treatment of cardiac rejection with OKT3., Study Design: Prospective clinical study., Patients: Twelve patients, whose pulmonary arterial resistances before transplantation were less than 400 dyn.s.cm-5, with haemodynamic and respiratory stability during the 4 hours before OKT3 administration., Method: Patients under preventive haemodynamic support with isoprenaline 0.05 micrograms.kg-1.min-1 and dopamine 3 micrograms.kg-1.min-1. Immunosuppressive treatment with azathioprine 5 mg.kg-1 at d0 and 3 mg.kg-1 at d1 and d2 and with methylprednisolone 720 mg at d0 and 240 mg at d1 and d2. OKT3, 5 mg administered i.v. at d0, d1, d2. Respiratory and haemodynamic variables were recorded prior to (T0), 30 min (T1) and 360 min (T2) after injection of OKT3., Result: Neither clinical nor radiological changes were observed after the OKT3 injections. At d0, T2, the heart rate increased and PaO2 and SaO2 decreased. At d1 and d2, T1, PaO2 decreased, and QS2QT at T1 d2 increased by nearly 3%., Conclusion: OKT3 does not result in major circulatory and haematosis changes, provided patients are selected, especially free of pretransplantation pulmonary hypertension. Prior to the treatment with OKT3, they should be in a satisfactory haemodynamic and respiratory status and receive high doses of corticosteroids.

To follow an heart transplantation, EBCT is more precise than ultrasonography and scintigraphy to calculate a stroke volume. In lung transplantation, it is important before surgery to know the value of right ventricule stroke volume in order to choice the surgical protocol. After lung transplantation SFE helps to follow the patient to look after complications, to drain a collection or to guide a biopsy. SFE contribution is discussed in rejection, infectious diseases, detection of immuno-induced carcinomas, in bronchiolitis obliterans and recurrence of the primitive disease.

The increase of organ transplantations during the last decades conjointly with the prescription of heavy immunosuppressive drugs, has led to an increased incidence of new invasive aspergillosis (IA). This study is a report of the Broussais Hospital experience from 1968 to 1993 on kidney, heart and heart and lungs transplantations. It concerns 21 IA cases. Incidence was 0.5% for kidney, 4.5% for heart and 18% for heart and lungs transplantations. The most important risk factors were the increase of immunosuppressive therapy (66% of the cases), neutropenia (19%), and renovation of the hospital wards (36%). Lung was the most frequent site of infection (95% of the cases), clinical symptoms were no significant. Diagnosis procedures were realised on biopsy (23%) and on bronchoalveolar lavage (66%). Usual amphotericin B treatment was disappointing: mortality rate of 77%, the liposomal preparation of the drug seemed to be more efficient: mortality rate of 50%. Itraconazole appeared to be used in succession with a careful adaptation of posology. Prophylactic amphotericin B in a local way (sprays and aerosols) led to a good efficiency jointly with the patient isolation during constructions in the hospital area.

Between 1984 and 1991 a total of 200 patients underwent heart transplantation in our unit. The records of 121 patients who were followed up for more than 1 year were reviewed for peripheral vascular abnormalities, which were found in 12 (9.9%). Most of these patients underwent transplantation for ischemic heart disease, and peripheral vascular disease preceded the heart transplantation in 80%. Although surgical risks are low in this setting, particular caution should be exercised to prevent septic complications in the femoral triangle. Among the risk factors studied, only elevated blood cholesterol was frequently found in the vascular patients before or after transplantation. Peripheral vascular involvement in heart transplant patients corresponds to the natural course of atheroma rather than to an accelerated process of atherosclerosis.