RESUMO
Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.
Assuntos
Proteína C-Reativa/metabolismo , Fibrose Pulmonar Idiopática/cirurgia , Transplante de Pulmão/fisiologia , Disfunção Primária do Enxerto/etiologia , Traumatismo por Reperfusão/complicações , Componente Amiloide P Sérico/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Imunidade Inata , Transplante de Pulmão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/sangue , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/cirurgia , Traumatismo por Reperfusão/imunologiaRESUMO
Primary graft dysfunction (PGD) is the leading cause of early posttransplant morbidity and mortality after lung transplantation. Clara cell secretory protein (CC16) is produced by the nonciliated lung epithelium and may serve as a plasma marker of epithelial cell injury. We hypothesized that elevated levels of CC16 would be associated with increased odds of PGD. We performed a prospective cohort study of 104 lung transplant recipients. Median plasma CC16 levels were determined at three time points: pretransplant and 6 and 24 h posttransplant. The primary outcome was the development of grade 3 PGD within the first 72 h after transplantation. Multivariable logistic regression was performed to evaluate for confounding by donor and recipient demographics and surgical characteristics. Twenty-nine patients (28%) developed grade 3 PGD within the first 72 h. The median CC16 level 6 h after transplant was significantly higher in patients with PGD [13.8 ng/mL (IQR 7.9, 30.4 ng/mL)] than in patients without PGD [8.2 ng/mL (IQR 4.5, 19.1 ng/mL)], p = 0.02. Elevated CC16 levels were associated with increased odds of PGD after lung transplantation. Damage to airway epithelium or altered alveolar permeability as a result of lung ischemia and reperfusion may explain this association.
Assuntos
Biomarcadores/sangue , Transplante de Pulmão/efeitos adversos , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/diagnóstico , Uteroglobina/sangue , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosRESUMO
Primary graft dysfunction (PGD) after lung transplantation causes significant morbidity and mortality. We aimed to determine the role of cytokines and chemokines in PGD. This is a multicenter case-control study of PGD in humans. A Luminex analysis was performed to determine plasma levels of 25 chemokines and cytokines before and at 6, 24, 48 and 72 h following allograft reperfusion in 25 cases (grade 3 PGD) and 25 controls (grade 0 PGD). Biomarker profiles were evaluated using a multivariable logistic regression and generalized estimating equations. PGD cases had higher levels of monocyte chemotactic protein-1 (MCP-1)/chemokine CC motif ligand 2 (CCL2) and interferon (IFN)-inducible protein (IP-10)/chemokine CXC motif ligand 10 (CXCL10) (both p < 0.05), suggesting recruitment of monocytes and effector T cells in PGD. In addition, PGD cases had lower levels of interleukin (IL-13) (p = 0.05) and higher levels of IL-2R (p = 0.05). Proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, and IFN-gamma decreased to very low levels after transplant in both PGD cases and controls, exhibiting no differences between the two groups. These findings were independent of clinical variables including diagnosis in multivariable analyses, but may be affected by cardiopulmonary bypass. Profound injury in clinical PGD is distinguished by the upregulation of selected chemokine pathways, which may useful for the prediction or early detection of PGD if confirmed in future studies.
Assuntos
Biomarcadores/sangue , Quimiocinas/sangue , Citocinas/sangue , Transplante de Pulmão/efeitos adversos , Disfunção Primária do Enxerto/etiologia , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Rejeição de Enxerto , Humanos , Mediadores da Inflamação , Masculino , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/sangue , Estudos Prospectivos , Adulto JovemRESUMO
While EBV PCR is used in the management of PTLD, the optimal primer set, relative importance of intracellular versus free plasma EBV, and the baseline profile in an organ transplant population remains unclear. We performed a prospective 2-arm trial utilizing an EBV PCR panel measuring LMP-1, EBER-1 and EBNA-1 in both free plasma as well as intracellular whole blood. Control Arm A consisted of 31 lung transplant patients and Arm B consisted of 35 transplant patients being evaluated for possible PTLD. In Arm A, 1/31 (3%) patients developed a transient plasma EBV load. Thirteen of 31 (42%) had detectable intracellular EBV. In Arm B, 17 (49%) patients were diagnosed with PTLD. Thirteen (76%) had EBV-positive PTLD with 12/13 (92%) having detectable EBV by PCR. The EBV PCR panel had a high sensitivity (92%), specificity (72%), positive predictive value (PPV) (71%) and negative predictive value (NPV) (93%) for diagnosing EBV-positive PTLD and followed patients' clinical course well (p < 0.001). Comparing the individual PCR assays, plasma EBNA PCR was superior with high sensitivity (77%), specificity (100%), PPV (100%) and NPV (86%). We conclude that EBV PCR is a useful test for managing PTLD patients. While plasma EBNA PCR is the best single assay for diagnosing and monitoring PTLD, the complete PCR panel is superior for ruling out its presence.
Assuntos
Herpesvirus Humano 4/genética , Transplante de Pulmão/efeitos adversos , Transtornos Linfoproliferativos/virologia , Reação em Cadeia da Polimerase/métodos , Antivirais/uso terapêutico , Primers do DNA , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Antígenos Nucleares do Vírus Epstein-Barr/sangue , Antígenos Nucleares do Vírus Epstein-Barr/genética , Humanos , Complicações Pós-Operatórias/virologia , Estudos Prospectivos , RNA Viral/sangue , RNA Viral/genética , Proteínas da Matriz Viral/sangue , Proteínas da Matriz Viral/genéticaRESUMO
A fundamental goal of lung transplantation is the regaining of functional capacity, yet little is known about what factors are associated with the achievement of this goal. The aim of this study is to test the association of clinical risk factors with functional status 1 year following lung transplantation. We conducted a cohort study of 321 lung transplants and assessed functionality by the distance achieved during a standard 6-min walk test (6MWT). Preoperative recipient risk factors were evaluated for association with functional status and adjusted for confounding using multivariable linear regression models. In these multivariable analyses, recipient female gender (p<0.001), recipient pretransplant body mass index (BMI) of greater than 27 kg/m2 (p=0.017) and shorter pretransplant 6MWT distances (p=0.006) were independently associated with shorter distances achieved during 6MWT after lung transplant, while cystic fibrosis (CF) (p=0.003), and bilateral lung transplant (p=0.014) were independently associated with longer distances achieved. Approximately 51% of the variance in 6MWT distance was explained by these risk factors in the linear regression models (R2=0.51). These findings may have implications in patient counseling, selection, procedure choice, and may lead to interventions aimed at improving the functional outcomes of lung transplantation.
Assuntos
Tolerância ao Exercício , Pneumopatias/fisiopatologia , Transplante de Pulmão , Pulmão/fisiopatologia , Adolescente , Adulto , Estudos de Coortes , Teste de Esforço , Feminino , Humanos , Pneumopatias/sangue , Pneumopatias/terapia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Valor Preditivo dos Testes , Fatores de RiscoRESUMO
BACKGROUND: Polyomavirus (primarily BK virus [BKV]) infection is an important cause of chronic renal dysfunction in renal transplant recipients, but its possible contribution to chronic renal dysfunction in non-renal solid organ transplant (NRSOT) recipients has not been fully explored. METHODS: We performed a prospective, cross-sectional study of consecutive NRSOT recipients with unexplained chronic renal dysfunction of at least a 3 months duration. Medical records were reviewed, and polymerase chain reaction was used to amplify BKV-specific sequences from serum and urine samples. The potential associations between various demographic and transplant variables and BKV infection were assessed. RESULTS: Thirty-four consecutive NRSOT recipients (23 lung, 8 liver, 2 heart, 1 heart-lung) with chronic renal dysfunction were enrolled at a median of 3.5 years (range 0.3-12.5 years) post transplantation. Five of the 34 (15%) patients had BKV viruria (range 1040-1.8 x 10(6) copies/mL), but none had BKV viremia. BK viruria was associated with mycophenolate mofetil use (5 of 19 [26%] vs. 0 of 15, P = 0.03) and a history of cytomegalovirus disease (3 of 4 [75%] vs. 2 of 30 [7%], P < 0.01). However, the mean estimated creatinine clearance was similar in patients with or without BKV viruria (49 vs. 47 mL/min). CONCLUSIONS: BKV viruria was present in a proportion of NRSOT patients with otherwise unexplained chronic renal dysfunction. The possibility that BKV infection might contribute to chronic renal dysfunction in this setting warrants further investigation.
Assuntos
Vírus BK/crescimento & desenvolvimento , Nefropatias/virologia , Infecções por Polyomavirus/virologia , Transplantes , Adulto , Idoso , Idoso de 80 Anos ou mais , Vírus BK/isolamento & purificação , Vírus BK/metabolismo , Estudos Transversais , Feminino , Humanos , Imunossupressores/uso terapêutico , Nefropatias/sangue , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/sangue , Infecções por Polyomavirus/etiologia , Estudos ProspectivosRESUMO
Information regarding treatment of post-transplant lymphoproliferative disease (PTLD) beyond reduction in immunosuppression (RI) is limited. We retrospectively evaluated patients receiving rituximab and/or chemotherapy for PTLD for response, time to treatment failure (TTF) and overall survival (OS). Thirty-five patients met inclusion criteria. Twenty-two underwent rituximab treatment, with overall response rate (ORR) 68%. Median TTF was not reached at 19 months and estimated OS was 31 months. In univariable analysis, Epstein-Barr virus (EBV) positivity predicted response and TTF. LDH elevation predicted shorter OS. No patient died of rituximab toxicity and all patients who progressed underwent further treatment with chemotherapy. Twenty-three patients received chemotherapy. ORR was 74%, median TTF was 10.5 months and estimated OS was 42 months. Prognostic factors for response included stage, LDH and allograft involvement by tumor. These factors and lack of complete response (CR) predicted poor survival. Twenty-six percent of the patients receiving chemotherapy died of toxicity. Rituximab and chemotherapy are effective in patients with PTLD who fail or do not tolerate RI. While rituximab is well tolerated, toxicity of chemotherapy is marked. PTLD patients requiring therapy beyond RI should be considered for rituximab, especially with EBV-positive disease. Chemotherapy should be reserved for patients who fail rituximab, have EBV-negative tumors or need a rapid response.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transtornos Linfoproliferativos/tratamento farmacológico , Transplante de Órgãos/efeitos adversos , Adulto , Idoso , Anticorpos Monoclonais Murinos , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Retrospectivos , Rituximab , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
Surgical advances, in conjunction with more effective immunosuppressive strategies, have propelled the field of lung transplantation forward and have made intermediate-term survival an achievable goal. Nonetheless, the post-transplant course is often marked by complications that threaten both the quality and duration of the recipient's life. Many of the medical complications that arise are the direct consequence of the need to administer potent immunosuppressive agents, with their attendant risks of infection, malignancy and drug toxicity. This article will review the major medical complications, excluding allograft rejection, which may be encountered in the lung transplant recipient. Familiarity with, and vigilance for, these problems should facilitate earlier recognition, more expeditious intervention and more favourable outcomes.