RESUMO
Preliminary evidence suggests that postoperative cognitive dysfunction (POCD) is common after lung transplantation. The impact of POCD on clinical outcomes has yet to be studied. The association between POCD and longer-term survival was therefore examined in a pilot study of posttransplantation survivors. Forty-nine participants from a prior randomized clinical trial underwent a neurocognitive assessment battery pretransplantation and 6 months posttransplantation, including assessments of the domains of Executive Function (Trail Making Test, Stroop, Digit Span), Processing Speed (Ruff 2 and 7 Test, Digit Symbol Substitution Test), and Verbal Memory (Verbal Paired Associates, Logical Memory, Animal Naming, and Controlled Oral Word Association Test). During a 13-year follow-up, 33 (67%) participants died. Greater neurocognition was associated with longer survival (hazard ratio [HR] = 0.49 [0.25-0.96], P = .039), and this association was strongest on tests assessing Processing Speed (HR = 0.58 [0.36-0.95], P = .03) and Executive Function (HR = 0.52 [0.28-0.97], P = .040). In addition, unadjusted analyses suggested an association between greater Memory performance and lower risk of CLAD (HR = 0.54 [0.29-1.00], P = .050). Declines in Executive Function tended to be predictive of worse survival. These preliminary findings suggest that postoperative neurocognition is predictive of subsequent mortality among lung transplant recipients. Further research is needed to confirm these findings in a larger sample and to examine mechanisms responsible for this relationship.
Assuntos
Transtornos Cognitivos/mortalidade , Rejeição de Enxerto/mortalidade , Transplante de Pulmão/efeitos adversos , Complicações Pós-Operatórias , Qualidade de Vida , Transtornos Cognitivos/etiologia , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Projetos Piloto , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
Lung transplantation has become an increasingly common treatment for patients with end-stage lung disease. Few studies have examined psychosocial risk factors for mortality in transplant recipients, despite evidence suggesting that elevated levels of negative affect are associated with greater mortality following major cardiac surgery. We therefore examined the relationship between negative affect early after lung transplantation and long-term survival in a sample of 132 lung transplant recipients (28 cystic fibrosis, 64 chronic obstructive pulmonary disease, 26 idiopathic pulmonary fibrosis, 14 other) followed for up to 13.5 years (median 7.4 years) following transplantation. Patients underwent both medical and psychosocial assessments 6 months following transplantation, which included the Beck Depression Inventory-II (BDI-II), Spielberger Anxiety Inventory, and General Health Questionnaire (GHQ). Over the course of follow-up, 80 (61%) participants died. Controlling for demographic factors, native lung disease, disease severity, family income, education level, social support, and frequency of posttransplant rejection, elevated symptoms of depression (BDI-II: HR = 1.31, p = 0.011) and distress (GHQ: HR = 1.28, p = 0.003) were associated with increased mortality. Higher levels of depression and general distress, but not anxiety, measured 6 months following lung transplantation are associated with increased mortality, independent of background characteristics and medical predictors.
Assuntos
Ansiedade/mortalidade , Transtorno Depressivo Maior/mortalidade , Transplante de Pulmão/psicologia , Complicações Pós-Operatórias , Transplantados/psicologia , Ansiedade/diagnóstico , Ansiedade/psicologia , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
The choice of a single or bilateral lung transplant for interstitial lung disease (ILD) is controversial, as surgical risk, long-term survival and organ allocation are competing factors. In an effort to balance risk and benefit, our center adopted a staged bilateral lung transplant approach for higher surgical risk ILD patients where the patient has a single lung transplant followed by a second single transplant at a later date. We sought to understand the surgical risk, organ allocation and early outcomes of these staged bilateral recipients as a group and in comparison to matched single and bilateral recipients. Our analysis demonstrates that staged bilateral lung transplant recipients (n = 12) have a higher lung allocation score (LAS), lower pulmonary function tests and a lower glomerular filtration rate prior to the first transplant compared to the second (p < 0.01). There was a shorter length of hospital stay for the second transplant (p = 0.02). The staged bilateral compared to the single and bilateral case-matched controls had comparable short-term survival (p = 0.20) and pulmonary function tests at 1 year. There was a higher incidence of renal injury in the conventional bilateral group compared to the single and staged bilateral groups. The staged bilateral procedure is a viable option in select ILD patients.
Assuntos
Sobrevivência de Enxerto , Tempo de Internação/estatística & dados numéricos , Doenças Pulmonares Intersticiais/mortalidade , Transplante de Pulmão/métodos , Complicações Pós-Operatórias , Adulto , Idoso , Feminino , Seguimentos , Humanos , Doenças Pulmonares Intersticiais/cirurgia , Transplante de Pulmão/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Testes de Função Respiratória , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Fatores de TempoRESUMO
Primary graft dysfunction (PGD) is a possible risk factor for bronchiolitis obliterans syndrome (BOS) following lung transplantation; however, the mechanism for any such association is poorly understood. Based on the association of TGF-ß with acute and chronic inflammatory disorders, we hypothesized that it might play a role in the continuum between PGD and BOS. Thus, the association between PGD and BOS was assessed in a single-center cohort of lung transplant recipients. Bronchoalveolar lavage fluid concentrations of TGF-ß and procollagen collected within 24 h of transplantation were compared across the spectrum of PGD, and incorporated into Cox models of BOS. Immunohistochemistry localized expression of TGF-ß and its receptor in early lung biopsies posttransplant. We found an association between PGD and BOS in both bilateral and single lung recipients with a hazard ratio of 3.07 (95% CI 1.76-5.38) for the most severe form of PGD. TGF-ß and procollagen concentrations were elevated during PGD (p < 0.01), and associated with increased rates of BOS. Expression of TGF-ß and its receptor localized to allograft infiltrating mononuclear and stromal cells, and the airway epithelium. These findings validate the association between PGD and the subsequent development of BOS, and suggest that this association may be mediated by receptor/TGF-ß biology.
Assuntos
Biomarcadores/metabolismo , Bronquiolite Obliterante/diagnóstico , Rejeição de Enxerto/diagnóstico , Transplante de Pulmão/efeitos adversos , Disfunção Primária do Enxerto/diagnóstico , Fator de Crescimento Transformador beta/metabolismo , Idoso , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/metabolismo , Estudos de Casos e Controles , Feminino , Seguimentos , Rejeição de Enxerto/sangue , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Técnicas Imunoenzimáticas , Pneumopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Disfunção Primária do Enxerto/etiologia , Disfunção Primária do Enxerto/metabolismo , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p < 5 × 10(-4) cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis.
Assuntos
Biomarcadores/análise , Variação Genética/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Transplante de Pulmão/efeitos adversos , Disfunção Primária do Enxerto/diagnóstico , Locos de Características Quantitativas , Adulto , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Inibidor 1 de Ativador de Plasminogênio/sangue , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/etiologia , Prognóstico , Estudos ProspectivosRESUMO
Chronic lung allograft dysfunction (CLAD) remains a major problem after lung transplantation with no definitive treatment except redo lung transplantation (re-LTx) in selected candidates. However, CLAD is not a homogeneous entity and different phenotypes exist. Therefore, we aimed to evaluate the effect of CLAD phenotypes on survival after re-LTx for CLAD. Patients who underwent re-LTx for respiratory failure secondary to CLAD in four LTx centers between 2003 and 2013 were included in this retrospective analysis. Bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD) were distinguished using pulmonary function, radiology and explant lung histopathology. Patient variables pre- and post-re-LTx were collected and analyzed. A total of 143 patients underwent re-LTx for CLAD resulting in 94 BOS (66%) and 49 rCLAD (34%) patients. Unadjusted and adjusted survival after re-LTx for rCLAD was worse compared to BOS (HR = 2.60, 1.59-4.24; p < 0.0001 and HR = 2.61, 1.51-4.51; p = 0.0006, respectively). Patients waiting at home prior to re-LTx experienced better survival compared to hospitalized patients (HR 0.40; 0.23-0.72; p = 0.0022). Patients with rCLAD redeveloped CLAD earlier and were more likely to redevelop rCLAD. Survival after re-LTx for rCLAD is worse compared to BOS. Consequently, re-LTx for rCLAD should be critically discussed, particularly when additional peri-operative risk factors are present.
Assuntos
Transplante de Pulmão , Disfunção Primária do Enxerto , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Taxa de Sobrevida , Adulto JovemRESUMO
Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP<40 mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4-7%, and high-risk a predicted PGD risk of 15-18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5% and 25%. We conclude that valid estimates of PGD risk can be produced using readily available clinical variables.
Assuntos
Transplante de Pulmão , Disfunção Primária do Enxerto , Adulto , Feminino , Humanos , Masculino , Fatores de RiscoRESUMO
This editorial puts into perspective the findings of the first randomized, controlled trial examining alemtuzumab induction for lung transplantation, and highlights the challenges encountered with alemtuzumab induction in other solid organs. See article by Jaksch et al on page 1839.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Transplante de Pulmão , Alemtuzumab , Feminino , Humanos , MasculinoRESUMO
As HLAs antibody detection technology has evolved, there is now detailed HLA antibody information available on prospective transplant recipients. Determining single antigen antibody specificity allows for a calculated panel reactive antibodies (cPRA) value, providing an estimate of the effective donor pool. For broadly sensitized lung transplant candidates (cPRA ≥ 80%), our center adopted a pretransplant multi-modal desensitization protocol in an effort to decrease the cPRA and expand the donor pool. This desensitization protocol included plasmapheresis, solumedrol, bortezomib and rituximab given in combination over 19 days followed by intravenous immunoglobulin. Eight of 18 candidates completed therapy with the primary reasons for early discontinuation being transplant (by avoiding unacceptable antigens) or thrombocytopenia. In a mixed-model analysis, there were no significant changes in PRA or cPRA changes over time with the protocol. A sub-analysis of the median fluorescence intensity (MFI) change indicated a small decline that was significant in antibodies with MFI 5000-10,000. Nine of 18 candidates subsequently had a transplant. Posttransplant survival in these nine recipients was comparable to other pretransplant-sensitized recipients who did not receive therapy. In summary, an aggressive multi-modal desensitization protocol does not significantly reduce pretransplant HLA antibodies in a broadly sensitized lung transplant candidate cohort.
Assuntos
Dessensibilização Imunológica , Rejeição de Enxerto/prevenção & controle , Hipersensibilidade/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Isoanticorpos/imunologia , Pneumopatias/cirurgia , Transplante de Pulmão , Idoso , Estudos de Coortes , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/mortalidade , Antígenos HLA/imunologia , Humanos , Imunoglobulinas Intravenosas/imunologia , Imunossupressores/uso terapêutico , Pneumopatias/mortalidade , Masculino , Pessoa de Meia-Idade , Plasmaferese , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM-1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p<0.001). CC-16 was associated with PGD in nonidiopathic pulmonary fibrosis (non-IPF) subjects (OR for highest quartile of CC-16: 2.87, 95% CI: 1.37, 6.00, p=0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p=0.59). After adjustment, preoperative CC-16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p=0.013) in non-IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients.
Assuntos
Biomarcadores/sangue , Pneumopatias/cirurgia , Transplante de Pulmão/efeitos adversos , Disfunção Primária do Enxerto/diagnóstico , Uteroglobina/sangue , Adulto , Idoso , Feminino , Seguimentos , Humanos , Pneumopatias/sangue , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/etiologia , Prognóstico , Estudos ProspectivosRESUMO
Bronchiolitis obliterans syndrome (BOS), a condition of irreversible small airway fibrosis, is the principal factor limiting long-term survival after lung transplantation. Bronchoscopy and bronchoalveolar lavage (BAL), techniques central to lung transplant clinical practice, provide a unique opportunity to interrogate the lung allograft during BOS development and identify potential disease mechanisms or biomarkers. Over the past 20 years, numerous studies have evaluated the BAL cellular composition, cytokine profiles and protein constituents in lung transplant recipients with BOS. To date, however, no summative evaluation of this literature has been reported. We developed and applied objective criteria to qualitatively rank the strength of associations between BAL parameters and BOS in order to provide a comprehensive and systematic assessment of the literature. Our analysis indicates that several BAL parameters, including neutrophil count, interleukin-8, alpha defensins and MMP-9, demonstrate highly replicable associations with BOS. Additionally, we suggest that considerable opportunity exists to increase the knowledge gained from BAL analyses in BOS through increased sample sizes, covariant adjustment and standardization of the BAL technique. Further efforts to leverage analysis of BAL constituents in BOS may offer great potential to provide additional in-depth and mechanistic insights into the pathogenesis of this complex disease.
Assuntos
Biomarcadores/análise , Bronquiolite Obliterante/diagnóstico , Líquido da Lavagem Broncoalveolar/química , Humanos , SíndromeRESUMO
Central airways stenosis (CAS) after lung transplant is a poorly understood complication. Objectives of this study were to determine if CAS was associated with chronic rejection or worse survival after transplant as well as to identify factors associated with CAS in a large cohort of lung transplant recipients. Lung transplant recipients transplanted at a single center were retrospectively reviewed for the development of CAS requiring airway dilation. A total of 467 subjects met inclusion criteria with 60 (13%) of these developing CAS requiring intervention. Of these 60 recipients, 22 (37%) had resolution of CAS with bronchoplasty alone, while 32 (53%) ultimately required stent placement. CAS that required intervention was not a risk factor for the development of bronchiolitis obliterans syndrome or worse overall survival. Significant risk factors for the subsequent development of CAS in a time-dependant multivariable model were pulmonary fungal infections and the need for postoperative tracheostomy. While CAS was not associated with BOS or worse survival, it remains an important complication after lung transplant with potentially preventable risk factors.
Assuntos
Bronquiolite Obliterante/etiologia , Constrição Patológica/etiologia , Transplante de Pulmão/efeitos adversos , Adulto , Bronquiolite Obliterante/diagnóstico , Constrição Patológica/terapia , Feminino , Volume Expiratório Forçado , Rejeição de Enxerto , Humanos , Transplante de Pulmão/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Espirometria , Stents , Transplante Homólogo , Resultado do TratamentoRESUMO
Aspergillus colonization after lung transplantation may increase the risk for bronchiolitis obliterans syndrome (BOS), a disease of small airways. We hypothesized that colonization with small conidia Aspergillus species would be associated with a greater risk of BOS, based upon an increased likelihood of deposition in small airways. We studied adult primary lung recipients from two large centers; 298 recipients at University of California, Los Angeles and 482 recipients at Duke University Medical Center. We grouped Aspergillus species by conidia diameter≤3.5 µm. We assessed the relationship of colonization with outcomes in Cox models. Pre-BOS colonization with small conidia Aspergillus species, but not large, was a risk factor for BOS (p=0.002, HR 1.44, 95% CI 1.14-1.82), along with acute rejection, single lung and Pseudomonas. Colonization with small conidia species also associated with risk of death (p=0.03, HR 1.30, 95% CI 1.03-1.64). Although other virulence traits besides conidia size may be important, we have demonstrated in two large independent cohorts that colonization with small conidia Aspergillus species increases the risk of BOS and death. Prospective evaluation of strategies to prevent Aspergillus colonization of small airways is warranted, with the goal of preserving lung allograft function as long as possible.
Assuntos
Aspergilose/complicações , Aspergillus/patogenicidade , Bronquiolite Obliterante/etiologia , Transplante de Pulmão/efeitos adversos , Idoso , Aspergilose/diagnóstico , Bronquiolite Obliterante/microbiologia , California , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , North Carolina , Modelos de Riscos Proporcionais , Infecções por Pseudomonas/diagnóstico , Testes de Função Respiratória , Fatores de Risco , Esporos Fúngicos/patogenicidadeRESUMO
To facilitate large-scale genetic mapping of the human genome, we have developed chromosome-specific sets of microsatellite marker loci suitable for use with a fluorescence-based automated DNA fragment analyser. We present 254 dinucleotide repeat marker loci (80% from the Généthon genetic linkage map) arranged into 39 sets, covering all 22 autosomes and the X chromosome. The average distance between adjacent markers is 13 centiMorgans, and less than 4% of the genome lies more than 20 cM from the nearest marker. Each set of microsatellites consists of up to nine marker loci, with allele size ranges that do not overlap. We selected marker loci on the basis of their reliability in the polymerase chain reaction, polymorphism content, map position and the accuracy with which alleles can be scored automatically by the Genotyper program.
Assuntos
Mapeamento Cromossômico/métodos , Sondas de DNA , DNA Satélite , Corantes Fluorescentes , Marcadores Genéticos , Genoma Humano , Polimorfismo Genético , Sequências Repetitivas de Ácido Nucleico , Automação , Sequência de Bases , Cromossomos Humanos , Feminino , Humanos , Masculino , Dados de Sequência Molecular , SoftwareRESUMO
Partial exclusion mapping of the nonobese (NOD) diabetic mouse genome has shown linkage of diabetes to at least five different chromosomes. We have now excluded almost all of the genome for the presence of susceptibility genes with fully recessive effects and have obtained evidence of linkage of ten distinct loci to diabetes or the prediabetic lesion, insulitis, indicative of a polygenic mode of inheritance. The relative importance of these loci and their interactions have been assessed using a new application of multiple polychotomous regression methods. A candidate disease gene, interleukin-2 (Il-2), which is closely linked to insulitis and diabetes, is shown to have a different sequence in NOD, including an insertion and a deletion of tandem repeat sequences which encode amino acid repeats in the mature protein.
Assuntos
Doenças Autoimunes/genética , Mapeamento Cromossômico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Interleucina-2/genética , Camundongos Endogâmicos NOD/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Cruzamentos Genéticos , DNA Complementar/genética , Feminino , Ligação Genética , Marcadores Genéticos , Masculino , Camundongos , Camundongos Endogâmicos C57BL/genética , Camundongos Endogâmicos NOD/imunologia , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Pancreatopatias/genética , Pancreatopatias/imunologia , Análise de RegressãoRESUMO
Cytomegalovirus (CMV) is the most prevalent opportunistic infection that occurs in lung-transplant recipients. In addition to its direct morbidity, multiple studies have demonstrated that CMV, in particular CMV pneumonia, is associated with an increased risk for chronic graft dysfunction manifested as bronchiolitis obliterans syndrome (BOS) and worse posttransplant survival. Therefore, prevention of CMV remains an important goal to improve long-term lung-transplant outcomes. Although centers often employed 3 months of prophylaxis in at-risk patients after lung transplantation, a significant proportion of patients still developed infection or disease after the discontinuation of prophylaxis, highlighting the need for more effective approaches to CMV prevention. A number of early single-center reports suggested benefit to extending prophylaxis to longer durations, but concerns regarding cost, late-onset CMV disease, viral resistance and bone marrow toxicity limited enthusiasm for longer durations. However, several recent studies including a multicenter, prospective, randomized, double-blinded clinical trial have demonstrated significant benefits to extending CMV prophylaxis beyond 3 months. Although some areas of controversy remain, the clinical implications of these recent studies suggest that extending prophylaxis with valganciclovir up to 12 months is clearly beneficial for CMV prevention after lung transplantation.
Assuntos
Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/patogenicidade , Transplante de Pulmão/efeitos adversos , HumanosRESUMO
Acute rejection (AR) is a common complication following lung transplantation and is an established risk factor for bronchiolitis obliterans syndrome (BOS). AR clinical presentation varies considerably and is sometimes associated with an acute decrease in forced expiratory volume in 1 s (FEV1). We hypothesized that lung transplant recipients who experience such spirometrically significant AR (SSAR), as defined by a ≥10% decline in FEV1 relative to the prior pulmonary function test, are subsequently at increased risk for BOS and worse overall survival. In a large single center cohort (n = 339), SSAR occurred in 79 subjects (23%) and significantly increased the risk for BOS (p < 0.0001, HR = 3.2, 95% CI 2.3-4.6) and death (p = 0.0001, HR = 2.3, 95% CI 1.5-3.5). These effects persisted after multivariate adjustment for pre-BOS AR and lymphocytic bronchiolitis burden. An analysis of the subset of patients who experienced severe SSAR (≥20% decline in FEV1) resulted in even greater hazards for BOS and death. Thus, we demonstrate a novel physiological measure that allows discrimination of patients at increased risk for worse posttransplant outcomes. Further studies are needed to determine mechanisms of airflow impairment and whether aggressive clinical interventions could improve post-SSAR outcomes.
Assuntos
Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/mortalidade , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/mortalidade , Transplante de Pulmão/efeitos adversos , Complicações Pós-Operatórias , Doença Aguda , Adulto , Bronquiolite Obliterante/etiologia , Feminino , Seguimentos , Volume Expiratório Forçado , Rejeição de Enxerto/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
Bronchiolitis obliterans syndrome (BOS) is a condition of progressive airflow obstruction that affects a majority of lung transplant recipients and limits long-term posttransplant survival. Although epithelial injury appears central to the development of BOS, little is known regarding the specific epithelial cell types that are affected in this condition. We hypothesized that BOS would involve preferential injury to the secretory Clara cells that function in innate defense and epithelial repair. To test this hypothesis, we assessed tissue transcript, tissue protein and lung fluid protein expression of Clara cell secretory protein (CCSP), a marker for Clara cells, in lung transplant recipients with BOS, BOS-free patients and in donor controls. Our results demonstrate that CCSP tissue transcript and protein expression are significantly reduced in lung transplant recipients with BOS compared to BOS-free or donor controls. In addition, we demonstrate that CCSP protein levels are significantly reduced in the lung fluid of patients with BOS compared to BOS-free controls, in cross-sectional and longitudinal analysis. Collectively, these complementary results illustrate that BOS involves a selective alteration in the distribution and function of bronchiolar Clara cells.
Assuntos
Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/patologia , Líquido da Lavagem Broncoalveolar/citologia , Células Epiteliais/metabolismo , Transplante de Pulmão/efeitos adversos , Uteroglobina/metabolismo , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Células Epiteliais/patologia , Feminino , Imunofluorescência , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Imuno-Histoquímica , Transplante de Pulmão/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Valores de Referência , Fatores de Risco , Índice de Gravidade de Doença , Síndrome , Uteroglobina/genéticaRESUMO
Discolouration of natural surface waters due to the humic component of dissolved organic carbon (DOC) is a costly problem for water supply companies. This paper reviews what is known about the impacts of prescribed moorland vegetation burning on water colour. Relevant research has taken place at three scales: laboratory experiments on peat cores, plot scale sampling of soil waters and catchment scale sampling of stream waters. While laboratory studies suggest burning increases colour production, the evidence from catchment and plot studies is contradictory. Plot studies suggest colour production may decrease or remain unchanged following burning although there is evidence for some transient changes. Catchment studies suggest prescribed moorland burning causes stream water colour to increase, although in most cases the evidence is not clear cut since most studies could not clearly disentangle the effects of burning from those of vegetation cover. The differences in findings between plot and catchment studies may be explained by: i) the short-term nature of some studies which do not measure long-term response and recovery times to burning; ii) the lack of colour measurements from shallow soil depths which contribute more to streamflow than soil water from deeper in the peat; and iii) the possibility of hydrological interactions occurring between different experimental plots at some sites. Additionally, the increase in recent patch burning in some catchments that has been statistically attributed by some authors to increases in stream water colour cannot be reconciled with theoretical calculations. When dilution with waters derived from other parts of the catchment are taken into account, large values of colour have to be theoretically derived from those recently burnt areas that occupy a small proportion of the catchment area in order to balance the change in stream water colour observed in recent years. Therefore, much further process-based work is required to properly investigate whether prescribed vegetation burning is a direct driver of enhanced colour and DOC in upland streams, rivers and lakes.
Assuntos
Cor , Incêndios , Água Doce , Qualidade da Água , Carbono , Água Subterrânea , Lagos , Rios , SoloRESUMO
Cytomegalovirus (CMV) is a common opportunistic infection after lung transplant. Despite effective antiviral medications to treat CMV, invasive CMV disease contributes to lung allograft dysfunction and worse survival. Efforts to prevent CMV have led to the use of valganciclovir prophylaxis for increasingly longer periods after transplant. A pivotal concern with long-term antiviral prophylaxis is that it may prevent or delay the development of CMV-specific immunity and increase the subsequent risk of late onset disease. To address this issue, we conducted a pilot study to determine if CMV-specific immunity was detectable in lung transplant recipients at risk for CMV while on antiviral prophylaxis. Utilizing polychromatic flow cytometry panels, CMV-specific immunity was determined by peripheral blood CD4 and CD8 T cell expression of cytokines in response to the HLA restricted CMV peptides pp65 and IE-1. We determined CMV seropositive lung transplant recipients on valganciclovir for a median of 6 months from transplant have a detectable polyfunctional CMV-specific T cell response which is comparable to seropositive recipients not on antiviral medications and to healthy seropositive nontransplant controls. Thus, valganciclovir prophylaxis does not appear to impair the development of CMV-specific immunity in lung transplantation.