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1.
J Heart Lung Transplant ; 43(4): 571-579, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38000763

RESUMO

BACKGROUND: Optimizing donor use and achieving maximal survival following lung transplantation (LTx) require a pretransplant assessment that identifies clinical, physiological, and psychosocial patient factors associated with both poor and optimal post-LTx survival. We examined the utility of a psychosocial tool, the Stanford Integrated Psychosocial Assessment for Transplant (SIPAT), to identify patient suitability for LTx, as well as its association with clinical outcomes before and after LTx. METHODS: This was a retrospective single-center study analyzing LTx assessment clinical variables (age, gender, diagnosis, functional capacity, nutrition, renal function), with a particular focus on the utility of the SIPAT score, to predict patient suitability for LTx. The same variables were analyzed against LTx waitlist mortality, as well as post-LTx survival. RESULTS: Over an 8-year period dating from December 2012, 914 patients (male 54.4%, mean age 55.2 years) underwent LTx assessment. Patients declined for LTx (n = 152, 16.6%) were older and had reduced functional capacity, nutritional markers, and renal function but had a higher SIPAT score. Once listed for LTx, a higher SIPAT score was not associated with waitlist mortality or reduced post-LTx survival. CONCLUSIONS: The SIPAT tool measures psychosocial suitability for transplantation that can be incorporated into a standardized assessment of LTx suitability. While patients with higher SIPAT score were more likely to be declined for LTx, the SIPAT score did not predict outcome in transplanted patients. A subgroup of patients with high SIPAT scores were successfully transplanted, suggesting that unfavorable psychosocial variables are potentially modifiable with a well-resourced multidisciplinary LTx team.


Assuntos
Transplante de Pulmão , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
2.
Transplantation ; 108(4): 1004-1014, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38044496

RESUMO

BACKGROUND: Chronic lung allograft dysfunction (CLAD), and especially bronchiolitis obliterans syndrome (BOS), remain dominant causes of morbidity and mortality after lung transplantation. Interest is growing in the forced oscillation technique, of which impulse oscillometry (IOS) is a form, as a tool to improve our understanding of these disorders. However, data remain limited and no longitudinal studies have been published, meaning there is no information regarding any capacity IOS may have for the early detection of CLAD. METHODS: We conducted a prospective longitudinal study enrolling a consecutive sample of adult bilateral lung transplant recipients with healthy lung allografts or CLAD and performed ongoing paired IOS and spirometry tests on a clinically determined basis. We assessed for correlations between IOS and spirometry and examined any predictive value either modality may hold for the early detection of BOS. RESULTS: We enrolled 91 patients and conducted testing for 43 mo, collecting 558 analyzable paired IOS and spirometry tests, with a median of 9 tests per subject (interquartile range, 5-12) and a median testing interval of 92 d (interquartile range, 62-161). Statistically significant moderate-to-strong correlations were demonstrated between all IOS parameters and spirometry, except resistance at 20 Hz, which is a proximal airway measure. No predictive value for the early detection of BOS was found for IOS or spirometry. CONCLUSIONS: This study presents the first longitudinal data from IOS after lung transplantation and adds considerably to the growing literature, showing unequivocal correlations with spirometry but failing to demonstrate a predictive value for BOS.


Assuntos
Síndrome de Bronquiolite Obliterante , Bronquiolite Obliterante , Adulto , Humanos , Oscilometria/métodos , Estudos Prospectivos , Estudos Longitudinais , Transplantados , Pulmão , Espirometria , Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/etiologia , Volume Expiratório Forçado
3.
Am J Transplant ; 23(12): 1922-1938, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37295720

RESUMO

In lung transplantation, antibody-mediated rejection (AMR) diagnosed using the International Society for Heart and Lung Transplantation criteria is uncommon compared with other organs, and previous studies failed to find molecular AMR (ABMR) in lung biopsies. However, understanding of ABMR has changed with the recognition that ABMR in kidney transplants is often donor-specific antibody (DSA)-negative and associated with natural killer (NK) cell transcripts. We therefore searched for a similar molecular ABMR-like state in transbronchial biopsies using gene expression microarray results from the INTERLUNG study (#NCT02812290). After optimizing rejection-selective transcript sets in a training set (N = 488), the resulting algorithms separated an NK cell-enriched molecular rejection-like state (NKRL) from T cell-mediated rejection (TCMR)/Mixed in a test set (N = 488). Applying this approach to all 896 transbronchial biopsies distinguished 3 groups: no rejection, TCMR/Mixed, and NKRL. Like TCMR/Mixed, NKRL had increased expression of all-rejection transcripts, but NKRL had increased expression of NK cell transcripts, whereas TCMR/Mixed had increased effector T cell and activated macrophage transcripts. NKRL was usually DSA-negative and not recognized as AMR clinically. TCMR/Mixed was associated with chronic lung allograft dysfunction, reduced one-second forced expiratory volume at the time of biopsy, and short-term graft failure, but NKRL was not. Thus, some lung transplants manifest a molecular state similar to DSA-negative ABMR in kidney and heart transplants, but its clinical significance must be established.


Assuntos
Transplante de Rim , Transplante de Pulmão , Células Matadoras Naturais , Transplante de Rim/efeitos adversos , Rim/patologia , Biópsia , Transplante de Pulmão/efeitos adversos , Anticorpos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia
4.
J Heart Lung Transplant ; 41(12): 1689-1699, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36163162

RESUMO

BACKGROUND: Many lung transplants fail due to chronic lung allograft dysfunction (CLAD). We recently showed that transbronchial biopsies (TBBs) from CLAD patients manifest severe parenchymal injury and dedifferentiation, distinct from time-dependent changes. The present study explored time-selective and CLAD-selective transcripts in mucosal biopsies from the third bronchial bifurcation (3BMBs), compared to those in TBBs. METHODS: We used genome-wide microarray measurements in 324 3BMBs to identify CLAD-selective changes as well as time-dependent changes and develop a CLAD classifier. CLAD-selective transcripts were identified with linear models for microarray data (limma) and were used to build an ensemble of 12 classifiers to predict CLAD. Hazard models and random forests were then used to predict the risk of graft loss using the CLAD classifier, transcript sets associated with rejection, injury, and time. RESULTS: T cell-mediated rejection and donor-specific antibody were increased in CLAD 3BMBs but most had no rejection. Like TBBs, 3BMBs showed a time-dependent increase in transcripts expressed in inflammatory cells that was not associated with CLAD or survival. Also like TBBs, the CLAD-selective transcripts in 3BMBs reflected severe parenchymal injury and dedifferentiation, not inflammation or rejection. While 3BMBs and TBBs did not overlap in their top 20 CLAD-selective transcripts, many CLAD-selective transcripts were significantly increased in both for example LOXL1, an enzyme controlling matrix remodeling. In Cox models for one-year survival, the 3BMB CLAD-selective transcripts and CLAD classifier predicted graft loss and correlated with CLAD stage. Many 3BMB CLAD-selective transcripts were also increased by injury in kidney transplants and correlated with decreased kidney survival, including LOXL1. CONCLUSIONS: Mucosal and transbronchial biopsies from CLAD patients reveal a diffuse molecular injury and dedifferentiation state that impacts prognosis and correlates with the physiologic disturbances. CLAD state in lung transplants shares features with failing kidney transplants, indicating elements shared by the injury responses of distressed organs.


Assuntos
Rejeição de Enxerto , Transplante de Pulmão , Humanos , Rejeição de Enxerto/genética , Estudos Retrospectivos , Pulmão , Aloenxertos , Mucosa
5.
Am J Transplant ; 22(4): 1054-1072, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34850543

RESUMO

Transplanted lungs suffer worse outcomes than other organ transplants with many developing chronic lung allograft dysfunction (CLAD), diagnosed by physiologic changes. Histology of transbronchial biopsies (TBB) yields little insight, and the molecular basis of CLAD is not defined. We hypothesized that gene expression in TBBs would reveal the nature of CLAD and distinguish CLAD from changes due simply to time posttransplant. Whole-genome mRNA profiling was performed with microarrays in 498 prospectively collected TBBs from the INTERLUNG study, 90 diagnosed as CLAD. Time was associated with increased expression of inflammation genes, for example, CD1E and immunoglobulins. After correcting for time, CLAD manifested not as inflammation but as parenchymal response-to-wounding, with increased expression of genes such as HIF1A, SERPINE2, and IGF1 that are increased in many injury and disease states and cancers, associated with development, angiogenesis, and epithelial response-to-wounding in pathway analysis. Fibrillar collagen genes were increased in CLAD, indicating matrix changes, and normal transcripts were decreased-dedifferentiation. Gene-based classifiers predicted CLAD with AUC 0.70 (no time-correction) and 0.87 (time-corrected). CLAD related gene sets and classifiers were strongly prognostic for graft failure and correlated with CLAD stage. Thus, in TBBs, molecular changes indicate that CLAD primarily reflects severe parenchymal injury-induced changes and dedifferentiation.


Assuntos
Transplante de Pulmão , Serpina E2 , Aloenxertos , Biópsia , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/genética , Pulmão , Transplante de Pulmão/efeitos adversos , Estudos Retrospectivos
6.
Transplant Proc ; 53(1): 296-302, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33039145

RESUMO

INTRODUCTION: Survival following lung transplantation (LTx) is limited by the development of chronic lung allograft dysfunction (CLAD), for which there are few effective therapies and no standardized management. Several small studies have demonstrated the effectiveness of extracorporeal photopheresis (ECP) as a therapeutic option for CLAD. METHODS: A retrospective descriptive audit of 12 LTx recipients who received rescue ECP for CLAD over 5 years (2013-2018) at the Alfred Hospital, Melbourne, Australia, was completed. Nonresponders to ECP were defined as patients who experienced a 20% decrease in forced expiratory volume (FEV1) within 6 weeks of commencing therapy. RESULTS: Mean time since LTx was 849 days and mean time since diagnosis of CLAD was 131 days. Fifty-eight percent of patients were male (n = 7) and 67% responded to ECP therapy (n = 8). Among responders, the mean (95% confidence interval) decline in FEV1 pre-ECP was 9.0 mL/day (5-12 mL/day), compared to 1.4 mL/day (0-4 mL/day) post-ECP (P = .01). Among nonresponders, mean (95% confidence interval) decline in FEV1 was 7.2 mL/day (4-10 mL/day) pre-ECP and 5.0 mL/day (3-7 mL/day) post ECP (P = .2). Nonresponders were more likely to be female (P = .01) and neutropenic (P = .005). Patients with prior exposure to anti-thymocyte globulin had a lowered response to ECP. CONCLUSION: Rescue ECP arrested the decline of lung function in 67% of patients with CLAD. Sex, pre-ECP neutrophil count, and exposure to anti-thymocyte globulin may help determine response to ECP. Future clinical trials are needed to confirm this effect, help predict response to therapy, and ultimately guide the placement of ECP in the treatment algorithm for CLAD.


Assuntos
Transplante de Pulmão/efeitos adversos , Fotoferese/métodos , Disfunção Primária do Enxerto/terapia , Adulto , Austrália , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
7.
J Heart Lung Transplant ; 39(1): 53-61, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31636045

RESUMO

BACKGROUND: A donor arterial PO2/FiO2 (P/F ratio) of less than the 300 threshold would frequently result in either exclusion of the donor or placement of the lungs on ex vivo lung perfusion (EVLP). The aim was to investigate the veracity of the P/F ratio threshold of 300 for donor lung acceptability. METHODS: In 93 brain dead lung donors, arterial blood gases were drawn in the intensive care unit (ICU) just before procurement and each of the 4 donor pulmonary veins in the operating room (OR). No donor lungs were rejected for transplantation based on the last ICU or OR P/F ratio, and EVLP was not used. The recipients were followed up 6 and 12 months following transplantation. RESULTS: There were 93 recipients of bilateral lung transplantation. An arterial P/F ratio of < 300 was largely driven by a low P/F ratio in the lower lobes. There were no differences between the recipients receiving donor lungs where the ICU P/F ratio was < 300 compared with ≥ 300 in the time to extubation, grade of primary graft dysfunction, pulmonary function at 6 and 12 months, and 12-month survival. CONCLUSIONS: From this study:(1) If a donor P/F threshold of 300 was adhered to, 36% would have been rejected, and (2) The donor P/F ratio threshold of 300 is excessively conservative and results in the wastage of donor lungs and the application of unnecessary EVLP.


Assuntos
Circulação Extracorpórea/métodos , Sobrevivência de Enxerto/fisiologia , Transplante de Pulmão/métodos , Pulmão/metabolismo , Preservação de Órgãos/métodos , Perfusão/métodos , Doadores de Tecidos , Adulto , Feminino , Seguimentos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
8.
Transplantation ; 103(8): 1689-1699, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30461721

RESUMO

BACKGROUND: In lung transplant recipients, immunosuppressive medications result in impaired antiviral immunity and a propensity for cytomegalovirus (CMV) reactivation within the lung allograft. Natural killer (NK) cells play a key role in immunity to CMV, with an increase in the proportion of NK cells expressing activating CD94-NKG2C receptors in the blood being a strong correlate of CMV infection. Whether a similar increase in NKG2C NK cells occurs in lung transplant recipients following CMV reactivation in the allograft and if such cells contribute to viral control remains unclear. METHODS: In this pilot study, we longitudinally assessed the frequency and phenotype of NKG2C NK cells in the blood and bronchoalveolar lavage (BAL) of lung transplant recipients and stratified recipients based on their risk of developing CMV disease. RESULTS: We observed an increase in the proportion of NKG2C NK cells in the blood and BAL of CMV high-risk patients, coincident with both the cessation of antiviral prophylaxis and subsequent detection of actively replicating CMV in the blood and lung allograft. Additionally, these NKG2C NK cells expressed killer-cell immunoglobulin-like receptors distinct from those of other NK subsets and BAL NKG2C NK cells possessed an activated phenotype. Finally, the frequency of NKG2C NK cells in the BAL may be inversely correlated with CMV blood titers. CONCLUSIONS: Monitoring the phenotype of NK cells postlung transplant may be a useful biomarker for monitoring patient levels of CMV immunity.


Assuntos
Anticorpos Antivirais/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Células Matadoras Naturais/imunologia , Transplante de Pulmão , Subfamília C de Receptores Semelhantes a Lectina de Células NK/sangue , Transplantados , Aloenxertos , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/química , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/virologia , Feminino , Citometria de Fluxo , Humanos , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Projetos Piloto
9.
Transpl Immunol ; 51: 73-75, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30321645

RESUMO

The use of algorithms such as HLAMatchmaker to redefine donor-recipient HLA matching is gaining increasing attention. Our research has previously demonstrated that higher HLA class II eplet mismatches correlated with the development of chronic lung allograft dysfunction (CLAD). In this study of lung transplant recipients we prospectively examined the association between donor-recipient HLA eplet mismatches as defined by HLAMatchmaker (version 2.1) and de-novo anti-HLA donor-specific antibody (DSA) formation, as assessed by single antigen-bead solid phase assay. HLA class II eplet mismatch, when split at the median for the cohort, predicted the development of de-novo HLA class II DSA at 3 months but not at 12 months. Having previously shown that high HLA class II eplet mismatches was associated with CLAD, we now show that the same factors are associated with de-novo HLA class II DSA post-transplant.


Assuntos
Rejeição de Enxerto/diagnóstico , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Teste de Histocompatibilidade/métodos , Transplante de Pulmão , Estudos de Coortes , Citometria de Fluxo , Sobrevivência de Enxerto , Antígenos HLA-DQ/sangue , Antígenos HLA-DR/sangue , Histocompatibilidade , Humanos , Separação Imunomagnética , Isoanticorpos/metabolismo , Prognóstico , Software , Transplantados
10.
Transpl Infect Dis ; 20(2): e12838, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29359876

RESUMO

Mycobacterium abscessus infection following lung transplantation has historically been associated with poor outcomes. We report a case of bilateral lung retransplantation complicated by obstruction of the right pulmonary artery secondary to M. abscessus mycotic aneurysm. Aggressive surgical management, including reconstruction of the right pulmonary artery, was undertaken with prolonged antimicrobial therapy. Thirty-six months later, antibiotics have been discontinued and the patient has stable soft tissue chest wall disease with good graft function. Mortality and morbidity associated with M. abscessus infection is considerable but this case illustrates that with aggressive early management, outcomes may be favorable.


Assuntos
Antibacterianos/uso terapêutico , Transplante de Pulmão/efeitos adversos , Infecções por Mycobacterium não Tuberculosas/etiologia , Infecções por Mycobacterium não Tuberculosas/terapia , Mycobacterium abscessus , Artéria Pulmonar/patologia , Adulto , Antibacterianos/administração & dosagem , Humanos , Masculino , Complicações Pós-Operatórias/terapia , Artéria Pulmonar/microbiologia , Artéria Pulmonar/cirurgia
11.
J Heart Lung Transplant ; 37(3): 323-331, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28320631

RESUMO

BACKGROUND: Recipient adolescent age for non-lung solid-organ transplantation is associated with higher rates of rejection, graft loss and mortality. Although there have been no studies specifically examining adolescent outcomes after lung transplantation (LTx), limited data from the International Society of Heart and Lung Transplantation (ISHLT) Registry suggest that a similar association may exist. Recently, adolescence has been defined as 10 to 24 years of age, taking into account the biologic and sociologic transitions that occur during this age interval. METHODS: The ISHLT Registry was used to examine the survival outcomes of LTx recipients 10 to 24 years of age between 2005 and 2013. Given the developmental changes that occur in adolescence, survival outcomes for the tertiles of adolescence (10 to 14, 15 to 19 and 20 to 24 years old) were also examined. RESULTS: Adolescents made up 9% (n = 2,319) of the 24,730 LTxs undertaken during the study period. Kaplan-Meier survival estimates at 3 years showed lower adolescent survival (65%) when compared with younger children (73%, p = 0.006) and adults 25 to 34 (75%, p < 0.00001) and 35 to 49 (71%, p < 0.00001) years of age, without a significant survival difference compared with those 50 to 65 years old. Critically, 15- to 19-year-old recipients had the poorest outcomes, with reduced 1-year survival (82%) compared with those 10 to 14 years old (88%, p = 0.02), and reduced 3-year survival (59%) compared with those 10 to 14 (73%, p < 0.00001) and 20 to 24 (66%, p < 0.0001) years old. CONCLUSIONS: Adolescent LTx recipients have poorer overall survival when compared with younger children and adults, with those 15 to 19 years old having the highest risk of death. This survival disparity among age groups likely reflects the difficult period of adolescence and its biologic and social transitions, which may influence both immunologic function and adherence.


Assuntos
Transplante de Pulmão , Complicações Pós-Operatórias/epidemiologia , Adolescente , Adulto , Fatores Etários , Criança , Feminino , Transplante de Coração , Humanos , Cooperação Internacional , Masculino , Sistema de Registros , Sociedades Médicas , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
12.
Clin Infect Dis ; 65(9): 1504-1508, 2017 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-29048510

RESUMO

BACKGROUND: Invasive and disseminated Mycoplasma hominis infections are well recognized but uncommon complications in solid organ transplant recipients. In a single center, a cluster of M. hominis infections were identified in lung transplant recipients from the same thoracic intensive care unit (ICU). We sought to determine the source(s) of these infections. METHODS: Medical records of the donor and infected transplant recipients were reviewed for clinical characteristics. Clinical specimens underwent routine processing with subculture on Mycoplasma-specific Hayflick agar. Mycoplasma hominis identification was confirmed using sequencing of the 16S ribosomal RNA gene. Mycoplasma hominis isolates were subjected to whole-genome sequencing on the Illumina NextSeq platform. RESULTS: Three lung transplant recipients presented with invasive M. hominis infections at multiple sites characterized by purulent infections without organisms detected by Gram staining. Each patient had a separate donor; however, pretransplant bronchoalveolar lavage fluid was only available from the donor for patient 1, which subsequently grew M. hominis. Phylo- and pangenomic analyses indicated that the isolates from the donor and the corresponding recipient (patient 1) were closely related and formed a distinct single clade. In contrast, isolates from patients 2 and 3 were unrelated and divergent from one another. CONCLUSIONS: Mycoplasma hominis should be considered a cause of donor-derived infection. Genomic data suggest donor-to-recipient transmission of M. hominis. Additional patients co-located in the ICU were found to have genetically unrelated M. hominis isolates, excluding patient-to-patient transmission.


Assuntos
Transplante de Pulmão/efeitos adversos , Infecções por Mycoplasma/etiologia , Infecções por Mycoplasma/microbiologia , Mycoplasma hominis/genética , Transplantados , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Doadores de Tecidos
13.
J Antimicrob Chemother ; 72(7): 2089-2092, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28369489

RESUMO

Objectives: This study describes the clinical outcomes and therapeutic drug monitoring (TDM) following posaconazole suspension pre-emptive therapy in lung transplant (LTx) recipients. Methods: This was a single-centre, retrospective cohort study evaluating posaconazole suspension pre-emptive therapy in LTx recipients between January 2009 and December 2015. Results: Forty-two LTx recipients were prescribed posaconazole suspension pre-emptively. Aspergillus fumigatus was the most commonly isolated fungal organism. Of the patients receiving posaconazole suspension as the initial antifungal post-LTx, 93% had eradication of colonization at 6 months after commencing therapy. In contrast, only 61% had eradication of fungal colonization when posaconazole suspension was administered following initial therapy with voriconazole. Posaconazole suspension appeared to be well tolerated, although one case was curtailed following concern about abnormal liver function and another due to nausea/vomiting. TDM was performed in 37 patients. The initial median (IQR) trough plasma concentration ( C min ) following 400 mg twice-daily posaconazole suspension was 0.78 (0.46-1.19) mg/L. Doses beyond 800 mg daily did not appear to result in a higher median C min. Conclusions: Early initiation of posaconazole suspension pre-emptive therapy in LTx recipients appears to be well tolerated and may potentially afford favourable clinical outcomes.


Assuntos
Antifúngicos/sangue , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/efeitos dos fármacos , Transplante de Pulmão , Transplantados , Triazóis/administração & dosagem , Triazóis/sangue , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Aspergilose/microbiologia , Aspergillus fumigatus/isolamento & purificação , Estudos de Coortes , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Suspensões , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Voriconazol/uso terapêutico
14.
PLoS One ; 11(1): e0140948, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26820896

RESUMO

BACKGROUND: Lung transplantation exposes the donated lung to a period of anoxia. Re-establishing the circulation after ischemia stimulates inflammation causing organ damage. Since our published data established that activin A is a key pro-inflammatory cytokine, we assessed the roles of activin A and B, and their binding protein, follistatin, in patients undergoing lung transplantation. METHODS: Sera from 46 patients participating in a published study of remote ischemia conditioning in lung transplantation were used. Serum activin A and B, follistatin and 11 other cytokines were measured in samples taken immediately after anaesthesia induction, after remote ischemia conditioning or sham treatment undertaken just prior to allograft reperfusion and during the subsequent 24 hours. RESULTS: Substantial increases in serum activin A, B and follistatin occurred after the baseline sample, taken before anaesthesia induction and peaked immediately after the remote ischemia conditioning/sham treatment. The levels remained elevated 15 minutes after lung transplantation declining thereafter reaching baseline 2 hours post-transplant. Activin B and follistatin concentrations were lower in patients receiving remote ischemia conditioning compared to sham treated patients but the magnitude of the decrease did not correlate with early transplant outcomes. CONCLUSIONS: We propose that the increases in the serum activin A, B and follistatin result from a combination of factors; the acute phase response, the reperfusion response and the use of heparin-based anti-coagulants.


Assuntos
Ativinas/sangue , Folistatina/sangue , Pneumopatias Obstrutivas/cirurgia , Transplante de Pulmão/métodos , Adulto , Citocinas/sangue , Feminino , Humanos , Precondicionamento Isquêmico , Pneumopatias Obstrutivas/sangue , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
15.
Curr Opin Organ Transplant ; 20(5): 492-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26262460

RESUMO

PURPOSE OF REVIEW: Pulmonary antibody-mediated rejection (AMR) while contributing to acute and chronic allograft dysfunction remains a diagnostic and therapeutic challenge. The diagnostic tenets upon which AMR is defined will be reviewed in the light of recent studies. RECENT FINDINGS: The introduction of solid phase assays such as the Luminex platform has provided a wealth of quantitative data on the presence of anti-human leukocyte antigen (HLA) donor-specific antibodies (DSA). Further studies are required to better define the relationship of circulating DSA and activation of proinflammatory immune pathways that result in allograft dysfunction. The limitations of C4d staining in defining AMR are highlighted from recent studies in lung transplantation and from the 2013 Banff meeting on renal transplantation. SUMMARY: The current challenge to the lung transplant community is to agree on a working definition of pulmonary AMR. Only then can we better appreciate the epidemiology, clinical phenotypes, and treatment of AMR.


Assuntos
Anticorpos/imunologia , Rejeição de Enxerto/imunologia , Epitopos/imunologia , Antígenos HLA/imunologia , Humanos , Transplante de Pulmão , Transplante Homólogo
16.
Respir Physiol Neurobiol ; 216: 28-34, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25981891

RESUMO

Long-term survival of lung transplant patients is limited, principally because of Bronchiolitis Obliterans Syndrome (BOS). BOS is primarily classified based on airflow obstruction however there is recent data to suggest that the rejection process can lead to a restrictive ventilatory defect with involvement of the pulmonary vasculature. This study evaluates perfusion heterogeneity in different BOS stages by measuring the relative dispersion (RD) of an arterial spin labelling MRI blood flow image. Acinar ventilation heterogeneity (Sacin) was determined using the Multiple Breath Nitrogen Washout technique. In 24 post transplant patients with a range of severity in BOS status, Sacin increased as BOS level rose from stage 0 to stage 3. In contrast, RD-perfusion was not elevated at BOS 1 and 2 combined compared to BOS 0 and becoming elevated only at BOS-3. However, RD-perfusion in BOS-0p was elevated compared to BOS-0, without an increase in Sacin. These results suggest that BOS-0p is different in nature from other BOS stages.


Assuntos
Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/etiologia , Transplante de Pulmão/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Transplantados , Bronquiolite Obliterante/prevenção & controle , Feminino , Seguimentos , Humanos , Processamento de Imagem Assistida por Computador , Imunossupressores/uso terapêutico , Masculino , Perfusão , Imagem de Perfusão , Espirometria
17.
J Heart Lung Transplant ; 34(1): 1-15, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25085497

RESUMO

The appropriate selection of lung transplant recipients is an important determinant of outcomes. This consensus document is an update of the recipient selection guidelines published in 2006. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) organized a Writing Committee of international experts to provide consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. A comprehensive search of the medical literature was conducted with the assistance of a medical librarian. Writing Committee members were assigned specific topics to research and discuss. The Chairs of the Writing Committee were responsible for evaluating the completeness of the literature search, providing editorial support for the manuscript, and organizing group discussions regarding its content. The consensus document makes specific recommendations regarding the timing of referral and of listing for lung transplantation. These recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation. In the absence of high-grade evidence to support decision making, these consensus guidelines remain part of a continuum of expert opinion based on available studies and personal experience. Some positions are immutable. Although transplant is rightly a treatment of last resort for end-stage lung disease, early referral allows proper evaluation and thorough patient education. Subsequent waiting list activation implies a tacit agreement that transplant offers a significant individual survival advantage. It is both the challenge and the responsibility of the transplant community globally to ensure organ allocation maximizes the potential benefits of a scarce resource, thereby achieving that advantage.


Assuntos
Consenso , Transplante de Coração-Pulmão/métodos , Seleção de Pacientes , Encaminhamento e Consulta/organização & administração , Sociedades Médicas , Doadores de Tecidos/provisão & distribuição , Listas de Espera , Humanos , Estudos Retrospectivos
18.
Transplantation ; 98(9): 927-30, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25369372

RESUMO

The lung transplant community continues to struggle with the diagnosis and management of antibody-mediated rejection. The four diagnostic tenets of donor-specific antibodies, C4d staining, histopathologic changes, and allograft dysfunction, which were largely derived from the early Banff meetings on renal transplantation, have somewhat arbitrarily been applied to lung transplantation. With the passage of time, it is increasingly apparent that merits of these diagnostic pillars are less robust in lung transplantation. In this article, we summarize some of the controversies and challenges surrounding the diagnosis of antibody-mediated rejection in lung transplantation.


Assuntos
Anticorpos/imunologia , Complemento C4b/imunologia , Rejeição de Enxerto/imunologia , Transplante de Pulmão/efeitos adversos , Fragmentos de Peptídeos/imunologia , Aloenxertos , Biomarcadores/metabolismo , Antígenos HLA/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Transplante de Rim , Pulmão/patologia , Resultado do Tratamento
19.
Transpl Immunol ; 31(2): 75-80, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25004453

RESUMO

BACKGROUND: The importance of antibody-mediated rejection (AMR) following lung transplantation remains contentious. In particular, the diagnostic criteria suggested to define AMR, namely the presence of donor-specific antibodies (DSA), C4d immunoreactivity, histological features and allograft dysfunction are not always readily applicable or confirmatory in lung transplantation. METHODS: In a retrospective single-center study of 255 lung transplant recipients (LTR), we identified 9 patients in whom a clinical diagnosis of AMR was made within 12months of transplant, and define the immunological, histological, clinical features, as well as the therapeutic response of this cohort. RESULTS: Nine LTR with AMR underwent combination therapy with high-dose intravenous corticosteroid, intravenous immunoglobulin, plasmapheresis and rituximab. Following therapy, while the total number of the original DSA dropped by 17%, and the median value of the mean fluorescence intensity (mfi) of the originally observed DSA decreased from 5292 (IQR 1319-12,754) to 2409 (IQR 920-6825) (p<0.001), clinical outcomes were variable with a number of patients progressing to either chronic lung allograft dysfunction or death within 12month. CONCLUSION: AMR in lung transplantation remains both a diagnostic and therapeutic challenge, but when clinically suspected is associated with a variable response to therapy and poor long-term outcomes.


Assuntos
Aloenxertos/imunologia , Anticorpos/sangue , Rejeição de Enxerto/imunologia , Transplante de Pulmão , Corticosteroides/uso terapêutico , Adulto , Anticorpos/imunologia , Anticorpos Monoclonais Murinos/uso terapêutico , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Terapia de Imunossupressão , Pulmão/imunologia , Pulmão/cirurgia , Masculino , Plasmaferese , Estudos Retrospectivos , Rituximab , Doadores de Tecidos
20.
J Heart Lung Transplant ; 32(11): 1123-30, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23932853

RESUMO

BACKGROUND: Xenotransplantation could provide a solution to the donor shortage that is currently the major barrier to solid-organ transplantation. The ability to breed pigs with multiple genetic modifications provides a unique opportunity to explore the immunologic challenges of pulmonary xenotransplantation. METHODS: Explanted lungs from wild-type and 3 groups of genetically modified pigs were studied: (i) α1,3-galactosyltransferase gene knockout (GTKO); (ii) GTKO pigs expressing the human complementary regulatory proteins CD55 and CD59 (GTKO/CD55-59); and (iii) GTKO pigs expressing both CD55-59 and CD39 (GTKO/CD55-59/CD39). The physiologic, immunologic and histologic properties of porcine lungs were evaluated on an ex vivo rig after perfusion with human blood. RESULTS: Lungs from genetically modified pigs demonstrated stable pulmonary vascular resistance and better oxygenation of the perfusate, and survived longer than wild-type lungs. Physiologic function was inversely correlated with the degree of platelet sequestration into the xenograft. Despite superior physiologic profiles, lungs from genetically modified pigs still showed evidence of intravascular thrombosis and coagulopathy after perfusion with human blood. CONCLUSIONS: The ability to breed pigs with multiple genetic modifications, and to evaluate lung physiology and histology in real-time on an ex vivo rig, represent significant advances toward better understanding the challenges inherent to pulmonary xenotransplantation.


Assuntos
Animais Geneticamente Modificados/fisiologia , Transplante de Pulmão , Pulmão/fisiologia , Modelos Animais , Suínos/genética , Transplante Heterólogo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Apirase/genética , Apirase/metabolismo , Antígenos CD55/genética , Antígenos CD55/metabolismo , Antígenos CD59/genética , Antígenos CD59/metabolismo , Feminino , Galactosiltransferases/deficiência , Galactosiltransferases/genética , Galactosiltransferases/metabolismo , Técnicas de Inativação de Genes , Humanos , Masculino , Perfusão , Resistência Vascular/fisiologia
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