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Shelley A Hall - One of the best experts on this subject based on the ideXlab platform.
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The New Direct Antiviral Agents and Hepatitis C in Thoracic Transplantation: Impact on Donors and Recipients
Current Transplantation Reports, 2018Co-Authors: Robert L. Gottlieb, Shelley A HallAbstract:Purpose of ReviewThe landscape of abdominal organ Transplantation has been altered by the emergence of curative direct-acting antiviral agents for hepatitis C. Expansion of the Thoracic donor pool to include the hearts and the lungs from hepatitis C-positive donors holds promise to increase available donor organs.Recent FindingsCase reports have documented separate lung and heart transplant patients who acquired, and then were cured of, donor-derived hepatitis C using these newer, more effective therapies. Single sites and national consortia are underway to help make this approach part of the standard-of-care. Pangenotypic therapies may simplify the paradigm.SummaryOrgans from donors with active hepatitis C viremia are likely suitable for transplant as long as the organ is otherwise acceptable. Best-practices for “informed-risk” transplant include a team-based approach and a selection of the antiviral regimen based on insurer’s formulary, potential drug interactions, and genotype.
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The New Direct Antiviral Agents and Hepatitis C in Thoracic Transplantation: Impact on Donors and Recipients
Current Transplantation Reports, 2018Co-Authors: Robert L. Gottlieb, Shelley A HallAbstract:Purpose of ReviewThe landscape of abdominal organ Transplantation has been altered by the emergence of curative direct-acting antiviral agents for hepatitis C. Expansion of the Thoracic donor pool to include the hearts and the lungs from hepatitis C-positive donors holds promise to increase available donor organs.Recent FindingsCase reports have documented separate lung and heart transplant patients who acquired, and then were cured of, donor-derived hepatitis C using these newer, more effective therapies. Single sites and national consortia are underway to help make this approach part of the standard-of-care. Pangenotypic therapies may simplify the paradigm.SummaryOrgans from donors with active hepatitis C viremia are likely suitable for transplant as long as the organ is otherwise acceptable. Best-practices for “informed-risk” transplant include a team-based approach and a selection of the antiviral regimen based on insurer’s formulary, potential drug interactions, and genotype.
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the new direct antiviral agents and hepatitis c in Thoracic Transplantation impact on donors and recipients
Current Transplantation Reports, 2018Co-Authors: Robert L. Gottlieb, Shelley A HallAbstract:The landscape of abdominal organ Transplantation has been altered by the emergence of curative direct-acting antiviral agents for hepatitis C. Expansion of the Thoracic donor pool to include the hearts and the lungs from hepatitis C-positive donors holds promise to increase available donor organs. Case reports have documented separate lung and heart transplant patients who acquired, and then were cured of, donor-derived hepatitis C using these newer, more effective therapies. Single sites and national consortia are underway to help make this approach part of the standard-of-care. Pangenotypic therapies may simplify the paradigm. Organs from donors with active hepatitis C viremia are likely suitable for transplant as long as the organ is otherwise acceptable. Best-practices for “informed-risk” transplant include a team-based approach and a selection of the antiviral regimen based on insurer’s formulary, potential drug interactions, and genotype.
Pierre Marquet - One of the best experts on this subject based on the ideXlab platform.
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Ciclosporin Population Pharmacokinetics and Bayesian Estimation in Thoracic Transplant Recipients
Clinical Pharmacokinetics, 2013Co-Authors: Dorothée Fruit, Pierre Marquet, Annick Rousseau, Catherine Amrein, Florence Rollé, Nassim Kamar, Laurent Sebbag, Michel Redonnet, Eric Epailly, Aurélie PrémaudAbstract: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
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Ciclosporin Population Pharmacokinetics and Bayesian Estimation in Thoracic Transplant Recipients
Clinical pharmacokinetics, 2013Co-Authors: Dorothée Fruit, Pierre Marquet, Annick Rousseau, Catherine Amrein, Florence Rollé, Nassim Kamar, Laurent Sebbag, Michel Redonnet, Eric Epailly, Aurélie PrémaudAbstract: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.
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Ciclosporin population pharmacokinetics and Bayesian estimation in Thoracic transplant recipients
2012Co-Authors: Dorothée Fruit, Pierre Marquet, Annick Rousseau, Catherine Amrein, Florence Rollé, Nassim Kamar, Laurent Sebbag, Michel Redonnet, Eric Epailly, Aurélie PrémaudAbstract: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: (i) to 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) to 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 nonlinear mixed effect modeling 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 during a dosage interval was built and evaluated in the validation dataset (69 profiles). Results: Ciclosporin pharmacokinetics was 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
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Pharmacokinetic Optimization of Immunosuppressive Therapy in Thoracic Transplantation: Part II
Clinical Pharmacokinetics, 2009Co-Authors: Caroline Monchaud, Pierre MarquetAbstract:Part I of this article, which appeared in the previous issue of the Journal, reviewed calcineurin inhibitors —ciclosporin and tacrolimus. In part II, we review the pharmacokinetics and therapeutic drug monitoring of mycophenolate and mammalian target of rapamycin inhibitors — sirolimus and everolimus — in Thoracic Transplantation, and we provide an overall discussion and suggest various areas for future study.
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Pharmacokinetic Optimization of Immunosuppressive Therapy in Thoracic Transplantation: Part I
Clinical Pharmacokinetics, 2009Co-Authors: Caroline Monchaud, Pierre MarquetAbstract:Although immunosuppressive treatments and therapeutic drug monitoring (TDM) have significantly contributed to the increased success of Thoracic Transplantation, there is currently no consensus on the best immunosuppressive strategies. Maintenance therapy typically consists of a triple-drug regimen including corticosteroids, a calcineurin inhibitor (ciclosporin or tacrolimus) and either a purine synthesis antagonist (mycophenolate mofetil or azathioprine) or a mammalian target of rapamycin inhibitor (sirolimus or everolimus). The incidence of acute and chronic rejection and of mortality after Thoracic Transplantation is still high compared with other types of solid organ Transplantation. The high allogenicity and immunogenicity of the lungs justify the use of higher doses of immunosuppressants, putting lung transplant recipients at a higher risk of drug-induced toxicities. All immunosuppressants are characterized by large intra- and interindividual variability of their pharmacokinetics and by a narrow therapeutic index. It is essential to know their pharmacokinetic properties and to use them for treatment individualization through TDM in order to improve the treatment outcome. Unlike the kidneys and the liver, the heart and the lungs are not directly involved in drug metabolism and elimination, which may be the cause of pharmacokinetic differences between patients from all of these transplant groups. TDM is mandatory for most immunosuppressants and has become an integral part of immunosuppressive drug therapy. It is usually based on trough concentration (C_0) monitoring, but other TDM tools include the area under the concentration-time curve (AUC) over the (12-hour) dosage interval or the AUC over the first 4 hours post-dose, as well as other single concentration-time points such as the concentration at 2 hours. Given the peculiarities of Thoracic Transplantation, a review of the pharmacokinetics and TDM of the main immunosuppressants used in Thoracic Transplantation is presented in this article. Even more so than in other solid organ transplant populations, their pharmacokinetics are characterized by wide intra- and interindividual variability in Thoracic transplant recipients. The pharmacokinetics of ciclosporin in heart and lung transplant recipients have been explored in a number of studies, but less is known about the pharmacokinetics of mycophenolate mofetil and tacrolimus in these populations, and there are hardly any studies on the pharmacokinetics of sirolimus and everolimus. Given the increased use of these molecules in Thoracic transplant recipients, their pharmacokinetics deserve to be explored in depth. There are very few data, some of which are conflicting, on the practices and outcomes of TDM of immunosuppressants after Thoracic Transplantation. The development of sophisticated TDM tools dedicated to Thoracic Transplantation are awaited in order to accurately evaluate the patients’ exposure to drugs in general and, in particular, to immunosuppressants. Finally, large cohort TDM studies need to be conducted in Thoracic transplant patients in order to identify the most predictive exposure indices and their target values, and to validate the clinical usefulness of improved TDM in these conditions. In part I of the article, we review the pharmacokinetics and TDM of calcineurin inhibitors. In part II, we will review the pharmacokinetics and TDM of mycophenolate and mammalian target of rapamycin inhibitors, and provide an overall discussion along with perspectives.
Robert L. Gottlieb - One of the best experts on this subject based on the ideXlab platform.
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The New Direct Antiviral Agents and Hepatitis C in Thoracic Transplantation: Impact on Donors and Recipients
Current Transplantation Reports, 2018Co-Authors: Robert L. Gottlieb, Shelley A HallAbstract:Purpose of ReviewThe landscape of abdominal organ Transplantation has been altered by the emergence of curative direct-acting antiviral agents for hepatitis C. Expansion of the Thoracic donor pool to include the hearts and the lungs from hepatitis C-positive donors holds promise to increase available donor organs.Recent FindingsCase reports have documented separate lung and heart transplant patients who acquired, and then were cured of, donor-derived hepatitis C using these newer, more effective therapies. Single sites and national consortia are underway to help make this approach part of the standard-of-care. Pangenotypic therapies may simplify the paradigm.SummaryOrgans from donors with active hepatitis C viremia are likely suitable for transplant as long as the organ is otherwise acceptable. Best-practices for “informed-risk” transplant include a team-based approach and a selection of the antiviral regimen based on insurer’s formulary, potential drug interactions, and genotype.
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The New Direct Antiviral Agents and Hepatitis C in Thoracic Transplantation: Impact on Donors and Recipients
Current Transplantation Reports, 2018Co-Authors: Robert L. Gottlieb, Shelley A HallAbstract:Purpose of ReviewThe landscape of abdominal organ Transplantation has been altered by the emergence of curative direct-acting antiviral agents for hepatitis C. Expansion of the Thoracic donor pool to include the hearts and the lungs from hepatitis C-positive donors holds promise to increase available donor organs.Recent FindingsCase reports have documented separate lung and heart transplant patients who acquired, and then were cured of, donor-derived hepatitis C using these newer, more effective therapies. Single sites and national consortia are underway to help make this approach part of the standard-of-care. Pangenotypic therapies may simplify the paradigm.SummaryOrgans from donors with active hepatitis C viremia are likely suitable for transplant as long as the organ is otherwise acceptable. Best-practices for “informed-risk” transplant include a team-based approach and a selection of the antiviral regimen based on insurer’s formulary, potential drug interactions, and genotype.
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the new direct antiviral agents and hepatitis c in Thoracic Transplantation impact on donors and recipients
Current Transplantation Reports, 2018Co-Authors: Robert L. Gottlieb, Shelley A HallAbstract:The landscape of abdominal organ Transplantation has been altered by the emergence of curative direct-acting antiviral agents for hepatitis C. Expansion of the Thoracic donor pool to include the hearts and the lungs from hepatitis C-positive donors holds promise to increase available donor organs. Case reports have documented separate lung and heart transplant patients who acquired, and then were cured of, donor-derived hepatitis C using these newer, more effective therapies. Single sites and national consortia are underway to help make this approach part of the standard-of-care. Pangenotypic therapies may simplify the paradigm. Organs from donors with active hepatitis C viremia are likely suitable for transplant as long as the organ is otherwise acceptable. Best-practices for “informed-risk” transplant include a team-based approach and a selection of the antiviral regimen based on insurer’s formulary, potential drug interactions, and genotype.
Heinrich Netz - One of the best experts on this subject based on the ideXlab platform.
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impaired cellular immune response to diphtheria and tetanus vaccines in children after Thoracic Transplantation
Pediatric Transplantation, 2011Co-Authors: Simon Urschel, Birgit D. Rieck, J. Birnbaum, Robert Dalla Pozza, Nikolaus Rieber, Katarzyna Januszewska, Alexandra Fuchs, Lori J. West, Heinrich NetzAbstract:Urschel S, Rieck BD, Birnbaum J, Dalla Pozza R, Rieber N, Januszewska K, Fuchs A, West LJ, Netz H, Belohradsky BH. Impaired cellular immune response to diphtheria and tetanus vaccines in children after Thoracic Transplantation. Pediatr Transplantation 2011: 15: 272–280. © 2011 John Wiley & Sons A/S. Abstract: Safety and immunogenicity of diphtheria and tetanus booster vaccination were evaluated in 28 children after Thoracic Transplantation. Adverse events were documented in a patient diary. Blood was collected prior to and four wk after vaccination. Specific antibody concentrations were measured by ELISA. Lymphocytes were investigated for expression of activation markers (CD25, HLA-DR) by flow cytometry and proliferation assays with and without stimulation. Post-vaccination antibody titers were higher than prevaccination (p < 0.001), with more patients having protective antibody levels against diphtheria (p < 0.02) and tetanus (p < 0.001). There was no increased proliferation in non-stimulated or stimulated cultures after vaccination. The number of T-lymphocytes activated by the vaccination antigens was similar pre- and post-vaccination, whereas HLA-DR-expression on stimulated and non-stimulated CD4+ T-cells increased significantly. Increase in antibodies was negatively correlated with tacrolimus dose, and impaired cellular immunity was associated with higher tacrolimus dose and steroid use. Adverse events were similar to the general population; serious adverse events and rejection did not occur. Vaccination with inactivated vaccines can be performed safely in immunosuppressed children after Thoracic Transplantation and induces protective antibody levels in the majority of patients. Impaired induction of specific cellular immunity is correlated with intensity of immunosuppression and may explain reduced sustainability of antibodies.
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Impaired cellular immune response to diphtheria and tetanus vaccines in children after Thoracic Transplantation
Pediatric transplantation, 2011Co-Authors: Simon Urschel, Birgit D. Rieck, J. Birnbaum, Robert Dalla Pozza, Nikolaus Rieber, Katarzyna Januszewska, Alexandra Fuchs, Lori J. West, Heinrich Netz, Bernd H. BelohradskyAbstract:Urschel S, Rieck BD, Birnbaum J, Dalla Pozza R, Rieber N, Januszewska K, Fuchs A, West LJ, Netz H, Belohradsky BH. Impaired cellular immune response to diphtheria and tetanus vaccines in children after Thoracic Transplantation. Pediatr Transplantation 2011: 15: 272–280. © 2011 John Wiley & Sons A/S. Abstract: Safety and immunogenicity of diphtheria and tetanus booster vaccination were evaluated in 28 children after Thoracic Transplantation. Adverse events were documented in a patient diary. Blood was collected prior to and four wk after vaccination. Specific antibody concentrations were measured by ELISA. Lymphocytes were investigated for expression of activation markers (CD25, HLA-DR) by flow cytometry and proliferation assays with and without stimulation. Post-vaccination antibody titers were higher than prevaccination (p
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lack of serologic immunity against vaccine preventable diseases in children after Thoracic Transplantation
Transplant International, 2009Co-Authors: Simon Urschel, J. Birnbaum, Alexandra Fuchs, Bernd H. Belohradsky, Sabine Cremer, Robert Dallapozza, Gundula Jager, Christoph Schmitz, Heinrich NetzAbstract:Summary We investigated whether children after heart- (HTx) or heart–lung Transplantation (HLTx) show protective antibody levels against recommended vaccinations, whether vaccination schedules are completed and which factors influence serologic immunity. We performed a cross sectional ELISA – quantification of specific antibodies in 46 patients after pediatric Thoracic Tx. Findings were correlated to vaccination history, age at Tx, clinical course and immunosuppressive regimen. We found protective antibody levels against diphtheria in 74% of patients, against tetanus in 22%, against Haemophilus influenzae type b in 30% and against Streptococcus pneumoniae in 59%. Antibody concentrations against live attenuated vaccines were significantly lower in children transplanted in the first 2 years of life. Antibodies were absent for measles in 55% of late – and 81% of early transplanted children, for mumps in 66%/94%, for rubella in 30%/56% and for Varicella in 34%/63%. We found significant correlation of low antibody concentrations and age at Tx. Patients without protective antibody concentrations had significantly longer use of steroids. Vaccination schedules were incomplete or delayed in the majority of patients associated with more days in hospital pre-Tx. Our study shows that closer adherence to preTransplantation vaccination schedules and also post-Transplantation monitoring of antibody levels are required in transplant patients.
Simon Urschel - One of the best experts on this subject based on the ideXlab platform.
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impaired cellular immune response to diphtheria and tetanus vaccines in children after Thoracic Transplantation
Pediatric Transplantation, 2011Co-Authors: Simon Urschel, Birgit D. Rieck, J. Birnbaum, Robert Dalla Pozza, Nikolaus Rieber, Katarzyna Januszewska, Alexandra Fuchs, Lori J. West, Heinrich NetzAbstract:Urschel S, Rieck BD, Birnbaum J, Dalla Pozza R, Rieber N, Januszewska K, Fuchs A, West LJ, Netz H, Belohradsky BH. Impaired cellular immune response to diphtheria and tetanus vaccines in children after Thoracic Transplantation. Pediatr Transplantation 2011: 15: 272–280. © 2011 John Wiley & Sons A/S. Abstract: Safety and immunogenicity of diphtheria and tetanus booster vaccination were evaluated in 28 children after Thoracic Transplantation. Adverse events were documented in a patient diary. Blood was collected prior to and four wk after vaccination. Specific antibody concentrations were measured by ELISA. Lymphocytes were investigated for expression of activation markers (CD25, HLA-DR) by flow cytometry and proliferation assays with and without stimulation. Post-vaccination antibody titers were higher than prevaccination (p < 0.001), with more patients having protective antibody levels against diphtheria (p < 0.02) and tetanus (p < 0.001). There was no increased proliferation in non-stimulated or stimulated cultures after vaccination. The number of T-lymphocytes activated by the vaccination antigens was similar pre- and post-vaccination, whereas HLA-DR-expression on stimulated and non-stimulated CD4+ T-cells increased significantly. Increase in antibodies was negatively correlated with tacrolimus dose, and impaired cellular immunity was associated with higher tacrolimus dose and steroid use. Adverse events were similar to the general population; serious adverse events and rejection did not occur. Vaccination with inactivated vaccines can be performed safely in immunosuppressed children after Thoracic Transplantation and induces protective antibody levels in the majority of patients. Impaired induction of specific cellular immunity is correlated with intensity of immunosuppression and may explain reduced sustainability of antibodies.
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Impaired cellular immune response to diphtheria and tetanus vaccines in children after Thoracic Transplantation
Pediatric transplantation, 2011Co-Authors: Simon Urschel, Birgit D. Rieck, J. Birnbaum, Robert Dalla Pozza, Nikolaus Rieber, Katarzyna Januszewska, Alexandra Fuchs, Lori J. West, Heinrich Netz, Bernd H. BelohradskyAbstract:Urschel S, Rieck BD, Birnbaum J, Dalla Pozza R, Rieber N, Januszewska K, Fuchs A, West LJ, Netz H, Belohradsky BH. Impaired cellular immune response to diphtheria and tetanus vaccines in children after Thoracic Transplantation. Pediatr Transplantation 2011: 15: 272–280. © 2011 John Wiley & Sons A/S. Abstract: Safety and immunogenicity of diphtheria and tetanus booster vaccination were evaluated in 28 children after Thoracic Transplantation. Adverse events were documented in a patient diary. Blood was collected prior to and four wk after vaccination. Specific antibody concentrations were measured by ELISA. Lymphocytes were investigated for expression of activation markers (CD25, HLA-DR) by flow cytometry and proliferation assays with and without stimulation. Post-vaccination antibody titers were higher than prevaccination (p
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lack of serologic immunity against vaccine preventable diseases in children after Thoracic Transplantation
Transplant International, 2009Co-Authors: Simon Urschel, J. Birnbaum, Alexandra Fuchs, Bernd H. Belohradsky, Sabine Cremer, Robert Dallapozza, Gundula Jager, Christoph Schmitz, Heinrich NetzAbstract:Summary We investigated whether children after heart- (HTx) or heart–lung Transplantation (HLTx) show protective antibody levels against recommended vaccinations, whether vaccination schedules are completed and which factors influence serologic immunity. We performed a cross sectional ELISA – quantification of specific antibodies in 46 patients after pediatric Thoracic Tx. Findings were correlated to vaccination history, age at Tx, clinical course and immunosuppressive regimen. We found protective antibody levels against diphtheria in 74% of patients, against tetanus in 22%, against Haemophilus influenzae type b in 30% and against Streptococcus pneumoniae in 59%. Antibody concentrations against live attenuated vaccines were significantly lower in children transplanted in the first 2 years of life. Antibodies were absent for measles in 55% of late – and 81% of early transplanted children, for mumps in 66%/94%, for rubella in 30%/56% and for Varicella in 34%/63%. We found significant correlation of low antibody concentrations and age at Tx. Patients without protective antibody concentrations had significantly longer use of steroids. Vaccination schedules were incomplete or delayed in the majority of patients associated with more days in hospital pre-Tx. Our study shows that closer adherence to preTransplantation vaccination schedules and also post-Transplantation monitoring of antibody levels are required in transplant patients.