R Guillemain

Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest), Lutetia Parisorum, Île-de-France, France

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Publications (128)503.37 Total impact

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    ABSTRACT: The optimal management of Mycobacterium chelonae disease in immunocompromised patients remains unclear. A combination of antimicrobial agents is recommended as monotherapy with clarithromycin has been associated with clinical failures due to acquired resistance. We aim to report the efficacy and tolerability of linezolid in association with clarithromycin for the treatment of M. chelonae infections in immunocompromised patients. We describe four immunocompromised patients treated by linezolid and clarithromycin for cutaneous M. chelonae disease. This combination was associated with rapid clinical efficacy in all patients with no relapse observed after a median follow-up of 2.25 years (1.4 years). However, this treatment was responsible for frequent adverse events including thrombocytopaenia, myalgia and mitochondrial toxicity. All adverse effects were reversible after linezolid discontinuation. We therefore suggest linezolid/clarithromycin combination as the initial therapeutic strategy for M. chelonae skin infections in immunocompromised patients. © 2015 European Academy of Dermatology and Venereology.
    Journal of the European Academy of Dermatology and Venereology 02/2015; · 2.69 Impact Factor
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    ABSTRACT: Rejection is one of the major causes of late cardiac allograft failure and at present can only be diagnosed by invasive endomyocardial biopsies. We sought to determine whether microRNA profiling could serve as a non-invasive biomarker of cardiac allograft rejection.
    European Heart Journal 08/2014; · 14.72 Impact Factor
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    ABSTRACT: Renal insufficiency (RI) is a frequent complication in heart transplant (HT) patients. The main objectives of the CARIN (Cardiac trAnsplantation and Renal INsufficiency) study were to follow the evolution of renal function after heart transplantation (HTx), to identify the factors associated with the decline of renal function, to describe the impact of RI on mortality during 3 years after the HT and to observe the renal profile of the prescriptions.French retrospective, multicentric, study. Data were collected for patients who received a HT between 2000 and 2005. Data collection was performed at 5 time points: before HTx (T0), 1(T1), 6(T6), 12 (T12) and 36 (T36) months after HTx. Glomerular Filtration Rate (GFR) was estimated with aMDRD formula. RI was defined as GFR<60 mL/min/1.73m²441 patients from 5 HT centers were included. The prevalences of RI were 28.8% (T0), 54.0% (T1), 50.4% (T6), 51.6% (T12), 59.6% (T36). Age and cyclosporine were independently linked to the decline of renal function. Hypertension and GFR<60 at T0 were independent risk factors of mortality. 48.7 to 64.7% of the non-immunosuppressive prescriptions were drugs that required dosage adjustment in RI patients or for which no data were available concerning administration in RI patients.RI is highly frequent after HTx. Because RI is a risk factor of mortality, any sparing renal strategies have to be undertaken.This article is protected by copyright. All rights reserved.
    Transplant International 05/2014; · 3.16 Impact Factor
  • Journal de Mycologie Médicale/Journal of Medical Mycology 03/2014; 24(1):72. · 0.40 Impact Factor
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    ABSTRACT: 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.
    Revue de Pneumologie Clinique 02/2014; · 0.19 Impact Factor
  • Transplantation 10/2013; 96(8):e58-9. · 3.78 Impact Factor
  • Néphrologie & Thérapeutique 09/2013; 9(5):348. · 0.55 Impact Factor
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    ABSTRACT: 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). 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). 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%). 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.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 08/2013; 32(8):769-76. · 5.61 Impact Factor
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    ABSTRACT: Purpose To examine myocardial inflammatory (MI) burden and phenotype of intravascular (IV) cells in EMBs with pathologic (p)AMR (Berry JHLT2011;30:601); to correlate both with pAMR grade, capillary C4d deposition and DSA status. Methods and Materials H&E and C4d-stained paraffin sections of 65 EMBs from 65 patients in 5 European heart transplant centers were reviewed and two groups identified: pAMR-positive/suspicious (grade 2: n=28; grade 1: n=6) or no pAMR (n=31). EMBs also showing acute cellular rejection ≥ 2R were excluded. Sections were stained for CD68, CD3, CD20 and CD138. Positive IV and interstitial mononuclear cells (MI burden) were counted in 5 microscopic fields at X40 magnification (area: .225 mm2) by 6 pathologists blinded to the diagnosis. Results were correlated with pAMR grade, C4d-positivity and DSA status. Results [Table 1] Conclusions Mean MI burden correlates with pAMR grade, C4d positivity, and DSA positivity. In pAMR equivalent numbers of IV T lymphocytes and macrophages were seen. CD68 antibody staining alone is not sufficient to characterize IV cells in pAMR. pAMR(-) vs pAMR(+) *p<.0001;** p=.0093;*** p=.0926;C4d(-) vs C4d(+) °p<<.0001;°°p=.004;°°°p=.0005;DSA(-) vs DSA(+) ^p<<.0001;^^p=.0833;^^^p=.0905View Within Article
    The Journal of Heart and Lung Transplantation 04/2013; 32(4):S19. · 5.61 Impact Factor
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    ABSTRACT: Purpose The pathological classification of AMR in EMB is based on histology (microvascular inflammation) and immunohistochemistry (deposition of C4d and/or CD68-positive intravascular macrophages). pAMR1, suspicious AMR, is divided in pAMR1(H+) based on histology findings alone and pAMR1(I+) based on immunopathologic findings alone. mTOR pathway activation, detected by endothelial expression of p70 S6 kinase (p70S6K) and phospho-S6 ribosomal protein (pS6RP) by immunohistochemistry, could be associated with endothelial cell involvement in AMR. The aim of this study was to correlate pS6RP and p70S6K expression with other AMR markers (intravascular macrophages at histology, C4d deposition, and DSA) and to assess the diagnostic value of immunohistochemical detection of pS6RP and p70S6K in microvessels of EMB. Methods and Materials 280 protocol EMB harvested during a 1 year period of time in a single institution were used. 32 EMB positive for AMR were included in the pAMR+ group encompassing 22 pAMR1(H+), 1 pAMR(I+), and 9 pAMR2. 32 EMB were randomly selected among the pAMR0 EMB and were the control group. Capillary expression of pS6RP and p70S6K was assessed by immunohistochemistry and ranked from grade 0 to grade 4, only grades 3 and 4 being considered positive. DSA were tested using Luminex technique. Results In the pAMR+ group, pS6RP and p70S6K were expressed in the endothelial cells of the EMB ranked pAMR2 (4/8 and 7/9 respectively), and also in grade pAMR1(H+) EMB (3/21 and 10/20 respectively). In the control group 1/32 EMB was positive. Microvascular expression of pS6RP and p70S6K was correlated with DSA (p=0.0190 and p=0.0076 respectively) and microvascular inflammation (p<0.05 and p<0.0001 respectively). Conclusions The endothelial expression of mTOR targets pS6RP and p70S6K is associated with AMR in both definite AMR grade pAMR2 and suspicious AMR grade pAMR1(H+), negative for C4d. That latter finding underscores the diagnostic value of pS6RP and p70S6K immunohistochemistry to characterize AMR in C4d-negative EMB.
    The Journal of Heart and Lung Transplantation 04/2013; 32(4):S20. · 5.61 Impact Factor
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    ABSTRACT: 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.
    PLoS ONE 03/2013; 8(3):e59634. · 3.53 Impact Factor
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    ABSTRACT: Therapeutic drug monitoring of tacrolimus is a major support to patient management and could help improve the outcome of lung transplant recipients, by minimizing the risk of rejections and infections. However, despite the wide use of tacrolimus as part of maintenance immunosuppressive regimens after lung transplantation, little is known about its pharmacokinetics in this population. Better knowledge of the pharmacokinetics of tacrolimus in lung transplant recipients, and the development of tools dedicated to its therapeutic drug monitoring, could thus help improve their outcome. The aims of this study were (i) to characterize the population pharmacokinetics of tacrolimus in lung transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator of the tacrolimus area under the blood concentration-time curve from time zero to 12 hours (AUC(12)) for its therapeutic drug monitoring in lung transplant recipients. A population pharmacokinetic model was developed by nonlinear mixed-effects modelling using NONMEM® version VI, from 182 tacrolimus full concentration-time profiles collected in 78 lung transplant recipients within the first year post-transplantation. Patient genotypes for the cytochrome P450 3A5 (CYP3A5) A6986G single nucleotide polymorphism (SNP) were characterized by TaqMan allelic discrimination. Patients were divided into an index dataset (n = 125 profiles) and a validation dataset (n = 57 profiles). A Bayesian estimator was derived from the final model using the index dataset, in order to determine the tacrolimus AUC(12) on the basis of a limited number of samples. The predictive performance of the Bayesian estimator was evaluated in the validation dataset by comparing the estimated AUC(12) with the trapezoidal AUC(12). Tacrolimus pharmacokinetics were described using a two-compartment model with Erlang absorption and first-order elimination. The model included cystic fibrosis (CF) and CYP3A5 polymorphism as covariates. The relative bioavailability in patients with CF was approximately 60% of the relative bioavailability observed in patients without CF, and the transfer rate constant between the transit compartments was 2-fold smaller in patients with CF than in those without CF (3.32 vs 7.06 h-1). The apparent clearance was 40% faster in CYP3A5 expressers than in non-expressers (24.5 vs 17.5 L/h). Good predictive performance was obtained with the Bayesian estimator developed using the final model and concentrations measured at 40 minutes and at 2 and 4 hours post-dose, as shown by the mean bias (1.1%, 95% CI -1.4, 3.7) and imprecision (9.8%) between the estimated and the trapezoidal AUC(12). The bias was >20% in 1.8% of patients. Population pharmacokinetic analysis showed that lung transplant patients with CF displayed lower bioavailability and a smaller transfer rate constant between transit compartments than those without CF, while the apparent clearance was faster in CYP3A5 expressers than in non-expressers. The Bayesian estimator developed in this study provides an accurate prediction of tacrolimus exposure in lung transplant patients, with and without CF, throughout the first year post-transplantation. This tool may allow routine tacrolimus dose individualization and may be used to conduct clinical trials on therapeutic drug monitoring of tacrolimus after lung transplantation.
    Clinical Pharmacokinetics 03/2012; 51(3):175-86. · 5.49 Impact Factor
  • American Journal of Transplantation. 01/2012; 12:476-476.
  • American Journal of Transplantation. 01/2012; 12:307-307.
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    American Journal of Transplantation 11/2011; · 6.19 Impact Factor
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    ABSTRACT: The immunosuppressive drug mycophenolate mofetil is used to prevent rejection after organ transplantation. In kidney transplant recipients, it has been demonstrated that adjustment of the mycophenolate mofetil dose on the basis of the area under the concentration-time curve (AUC) of mycophenolic acid (MPA), the active moiety of mycophenolate mofetil, improves the clinical outcome. Because of the high risks of rejections and infections in lung transplant recipients, therapeutic drug monitoring of the MPA AUC might be even more useful in these patients. The aims of this study were to characterize the pharmacokinetics of MPA in lung and kidney transplant recipients, describe the differences between the two populations and develop a Bayesian estimator of the MPA AUC in lung transplant recipients. In total, 460 MPA concentration-time profiles from 41 lung transplant recipients and 116 kidney transplant recipients were included. Nonlinear mixed-effects modelling was used to develop a population pharmacokinetic model. Patients were divided into an index dataset and a validation dataset. The pharmacokinetic model derived from the index dataset was used to develop a Bayesian estimator, which was validated using the 35 lung transplant recipients' profiles from the validation dataset. MPA pharmacokinetics were described using a two-compartment model with lag time, first-order absorption and first-order elimination. The influence of ciclosporin co-treatment and the changes over time post-transplantation were included in the model. Lung transplant recipients had, on average, a 53% slower absorption rate and 50% faster MPA apparent oral clearance than kidney transplant recipients (p < 0.001). In lung transplant recipients, the bioavailability was, on average, 31% lower in patients with cystic fibrosis than in patients without cystic fibrosis (p < 0.001). The Bayesian estimator developed using the population pharmacokinetic model--and taking into account ciclosporin co-treatment, cystic fibrosis and time post-transplantation, with concentrations measured at 0, 1 and 4 hours after mycophenolate mofetil dose administration--resulted in a non-significant bias and mean imprecision of 5.8 mg · h/L. This higher imprecision compared with those of similar estimators that have previously been developed in kidney transplantation might have been caused by the high MPA pharmacokinetic variability seen in the lung transplant recipients and by the fact that a large proportion of the patients did not receive ciclosporin, which reduces variability in the elimination phase of MPA by blocking its enterohepatic cycling. Lung transplant recipients have a slower MPA absorption rate and faster apparent oral clearance than kidney transplant recipients, while cystic fibrosis results in lower MPA bioavailability. A Bayesian estimator using MPA concentration-time samples at 0, 1 and 4 hours post-dose had the best predictive performance.
    Clinical Pharmacokinetics 11/2011; 51(1):29-39. · 5.49 Impact Factor
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    ABSTRACT: 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.
    American Journal of Transplantation 06/2011; 11(7):1478-87. · 6.19 Impact Factor
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    ABSTRACT: 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.
    Asian cardiovascular & thoracic annals 06/2011; 19(3-4):202-6.
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    ABSTRACT: 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.
    Clinical Transplantation 04/2011; 25(4):E430-6. · 1.49 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2011; 30(4). · 5.61 Impact Factor

Publication Stats

901 Citations
503.37 Total Impact Points

Institutions

  • 2003–2015
    • Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest)
      • • Service d’Anesthésie-Réanimation
      • • Service de Pharmacie
      • • Service de Pharmacologie
      • • Service de Chirurgie Cardiovasculaire
      Lutetia Parisorum, Île-de-France, France
  • 2009
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Paris, Ile-de-France, France