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1.
Am J Respir Cell Mol Biol ; 62(3): 364-372, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31647878

RESUMO

The immune system is designed to robustly respond to pathogenic stimuli but to be tolerant to endogenous ligands to not trigger autoimmunity. Here, we studied an endogenous damage-associated molecular pattern, mitochondrial DNA (mtDNA), during primary graft dysfunction (PGD) after lung transplantation. We hypothesized that cell-free mtDNA released during lung ischemia-reperfusion triggers neutrophil extracellular trap (NET) formation via TLR9 signaling. We found that mtDNA increases in the BAL fluid of experimental PGD (prolonged cold ischemia followed by orthotopic lung transplantation) and not in control transplants with minimal warm ischemia. The adoptive transfer of mtDNA into the minimal warm ischemia graft immediately before lung anastomosis induces NET formation and lung injury. TLR9 deficiency in neutrophils prevents mtDNA-induced NETs, and TLR9 deficiency in either the lung donor or recipient decreases NET formation and lung injury in the PGD model. Compared with human lung transplant recipients without PGD, severe PGD was associated with high levels of BAL mtDNA and NETs, with evidence of relative deficiency in DNaseI. We conclude that mtDNA released during lung ischemia-reperfusion triggers TLR9-dependent NET formation and drives lung injury. In PGD, DNaseI therapy has a potential dual benefit of neutralizing a major NET trigger (mtDNA) in addition to dismantling pathogenic NETs.

2.
Am J Health Syst Pharm ; 76(24): 2019-2027, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31696925

RESUMO

PURPOSE: Tacrolimus is a nephrotoxic immunosuppressant historically monitored via enzyme-based immunoassay (IA). After 2011, the 2 largest laboratory companies in the United States implemented tacrolimus quantification by liquid chromatography-mass spectrometry (LC-MS); this method excludes metabolites, potentially resulting in lower quantified drug concentrations. We sought to determine if tacrolimus therapeutic drug monitoring via LC-MS, as performed using trough targets originally derived from IA values, influences clinical outcomes. METHODS: In a single-center retrospective cohort study of lung transplant recipients, risks of acute kidney injury, acute renal failure, and new-onset diabetes after transplantation, as well as chronic lung allograft dysfunction-free survival, were compared in 82 subjects monitored by LC-MS and 102 subjects monitored by IA using Cox proportional hazard models adjusted for age, sex, baseline renal function, and race. RESULTS: LC-MS-based monitoring was associated with a greater risk of acute kidney injury (adjusted hazard ratio, 1.65; 95% confidence interval, 1.02-2.67). No statistically significant differences in risks of acute renal failure and new-onset diabetes after transplantation were observed. CONCLUSION: Although LC-MS provides a more accurate representation of the blood concentration of the parent compound tacrolimus exclusive of metabolite, established cut points for tacrolimus dosing may need to be adjusted to account for the increased risk of renal injury.

3.
JCI Insight ; 4(22)2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31613800

RESUMO

BACKGROUNDInnate immune activation impacts lung transplant outcomes. Dectin-1 is an innate receptor important for pathogen recognition. We hypothesized that genotypes reducing dectin-1 activity would be associated with infection, graft dysfunction, and death in lung transplant recipients.METHODSWe assessed the rs16910526 CLEC7A gene polymorphism Y238X, which results in dectin-1 truncation, in 321 lung allograft recipients at a single institution and in 1,129 lung allograft recipients in the multicenter Lung Transplant Outcomes Group (LTOG) cohort. Differences in dectin-1 mRNA, cytokines, protein levels, immunophenotypes, and clinical factors were assessed.RESULTSY238X carriers had decreased dectin-1 mRNA expression (P = 0.0001), decreased soluble dectin-1 protein concentrations in bronchoalveolar lavage (P = 0.008) and plasma (P = 0.04), and decreased monocyte surface dectin-1 (P = 0.01) compared with wild-type subjects. Y238X carriers had an increased risk of fungal pathogens (HR 1.17, CI 1.0-1.4), an increased risk of graft dysfunction or death (HR 1.6, CI 1.0-2.6), as well increased mortality in the UCSF cohort (HR 1.8, CI 1.1-3.8) and in the LTOG cohort (HR 1.3, CI 1.1-1.6), compared with wild-type CLEC7A subjects.CONCLUSIONIncreased rates of graft dysfunction and death associated with this dectin-1 polymorphism may be amplified by immunosuppression that drives higher fungal burden from compromised pathogen recognition.FUNDINGThe UCSF Nina Ireland Program for Lung Health Innovative Grant program, the Clinical Sciences Research & Development Service of the VA Office of Research and Development, and the Joel D. Cooper Career Development Award from the International Society for Heart and Lung Transplantation.

4.
J Heart Lung Transplant ; 38(12): 1246-1256, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31474492

RESUMO

BACKGROUND: Obesity is associated with an increased risk of primary graft dysfunction (PGD) after lung transplantation. The contribution of specific adipose tissue depots is unknown. METHODS: We performed a prospective cohort study of adult lung transplant recipients at 4 U.S. transplant centers. We measured cross-sectional areas of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on chest and abdominal computed tomography (CT) scans and indexed each measurement to height.2 We used logistic regression to examine the associations of adipose indices and adipose classes with grade 3 PGD at 48 or 72 hours, and Cox proportional hazards models to examine survival. We used latent class analyses to identify the patterns of adipose distribution. We examined the associations of adipose indices with plasma biomarkers of obesity and PGD. RESULTS: A total of 262 and 117 subjects had available chest CT scans and underwent protocol abdominal CT scans, respectively. In the adjusted models, a greater abdominal SAT index was associated with an increased risk of PGD (odds ratio 1.9, 95% CI 1.02-3.4, p = 0.04) but not with survival time. VAT indices were not associated with PGD risk or survival time. A greater abdominal SAT index correlated with greater pre- and post-transplant leptin (r = 0.61, p < 0.001, and r = 0.44, p < 0.001), pre-transplant IL-1RA (r = 0.25, p = 0.04), and post-transplant ICAM-1 (r = 0.25, p = 0.04). We identified 3 latent patterns of adiposity. The class defined by high thoracic and abdominal SAT had the greatest risk of PGD. CONCLUSIONS: Subcutaneous, but not visceral, adiposity is associated with an increased risk of PGD after lung transplantation.

5.
Lancet Respir Med ; 7(11): 975-984, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31378427

RESUMO

BACKGROUND: Donor lung use for transplantation is the lowest among solid organ tranplants because of several complex and multifactorial reasons; one area that could have a substantial role is the limited capabilities of cold ischaemic storage. The aim of the EXPAND trial was to evaluate the efficacy of normothermic portable Organ Care System (OCS) Lung perfusion and ventilation on donor lung use from extended-criteria donors and donors after circulatory death, which are rarely used. METHODS: In this single-arm, pivotal trial done in eight institutions across the USA, Germany, and Belgium, lungs from extended-criteria donors were included if fulfilling one or more of the following criteria: a ratio of partial pressure of arterial oxygen (PaO2) to fractional concentration of oxygen inspired air (FiO2) in the donor lung of 300 mm Hg or less; expected ischaemic time longer than 6 h; donor age 55 years or older; or lungs from donors after circulatory death that were recruited and assessed using OCS Lung. Lungs were transplanted if they showed stability of OCS Lung variables, PaO2:FiO2 was more than 300 mm Hg, and they were accepted by the transplanting surgeon. Patients were adult bilateral lung transplant recipients. The primary efficacy endpoint was a composite of patient survival at day 30 post-transplant and absence of The International Society for Heart & Lung Tranplantation primary-graft dysfunction grade 3 (PGD3) within 72 h post-transplantation, with a prespecified objective performance goal of 65%. The primary analysis population was all transplanted recipients. This trial is registered with ClinicalTrials.gov, number NCT01963780, and is now complete. FINDINGS: Between Jan 23, 2014, and Oct 23, 2016, 93 lung pairs were perfused, ventilated, and assessed on the OCS Lung. 12 lungs did not meet OCS transplantation criteria so 81 lungs were suitable for transplantation. Two lungs were excluded for logistical reasons, hence 79 (87%) of eligible lungs were transplanted. The primary endpoint was achieved in 43 (54%) of 79 patients and did not meet the objective performance goal. 35 (44%) of 79 patients had PGD3 within the initial 72 h. 78 (99%) of 79 patients had survived at 30 days post-transplant. The mean number of lung graft-related serious adverse events (respiratory failure and major pulmonary-related infection) was 0·3 events per patient (SD 0·5). INTERPRETATION: Despite missing the objective primary endpoint, the portable OCS Lung resulted in 87% donor lung use for transplantation with excellent clinical outcomes. Many lungs declined by other transplant centres were successfully transplanted using this new technology, which implies its use has the potential to increase the number of lung transplants performed worldwide. Whether similar outcomes could be obtained if these lungs were preserved on ice is unknown and remains an area for future research. FUNDING: TransMedics Inc.

6.
Am J Transplant ; 19(11): 3155-3161, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31278829

RESUMO

Frailty is a state of decreased physiologic reserve associated with poor outcomes before and after lung transplantation. Obesity, particularly central obesity characterized by excess proinflammatory visceral adipose tissue (VAT), is associated with incident frailty in middle-aged and older adults. The association between VAT and frailty in advanced lung disease, however, is unknown. In two, nonoverlapping multicenter cohorts of adults listed for lung transplantation, we measured VAT area on bioelectrical impedance assay (BIA) in one cohort and cross-sectional VAT and subcutaneous adipose tissue (SAT) areas on abdominal computed tomography (CT) in the other. We identified a nonlinear relationship between greater VAT by BIA and frailty. In fully adjusted piecewise regression models, every 20 cm2 increase in VAT area was associated with 50% increased odds of frailty in subjects with high VAT (95% CI 1.2-1.9, P < .001), and 10% decreased odds of frailty (95% CI 0.7-1.04, P = .12) in subjects with low VAT. Compared to frail subjects with low VAT, those with high VAT were more likely to have low grip strength and less likely to have weight loss, suggesting that mechanisms of frailty may differ by VAT. Further investigation of mechanisms linking VAT and frailty may identify new targets for prevention and treatment.

7.
J Heart Lung Transplant ; 38(7): 699-707, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31005571

RESUMO

BACKGROUND: Frailty is common in adults with advanced lung disease and is associated with death before and after lung transplantation. We aimed to determine whether frailty changes from before to after the lung transplant. METHODS: In a single-center, prospective cohort study among adults undergoing lung transplantation from 2010 to 2017, we assessed frailty by the Short Physical Performance Battery (SPPB; higher scores reflect less frailty) and Fried Frailty Phenotype (FFP; higher scores reflect greater frailty) before and repeatedly up to 36 months after transplant. We tested for changes in frailty scores over time using segmented mixed effects models, adjusting for age, sex, and diagnosis. We quantified the proportion of subjects transitioning between frailty states (frail vs not frail) from before to after the transplant. RESULTS: In 246 subjects, changes in frailty occurred within the first 6 post-operative months and remained stable thereafter. The overall change in frailty was attributable to improvements among those subjects who were frail before transplant. They experienced a 5.1-point improvement in SPPB (95% confidence interval [CI] 4.6-5.7) and a 1.8-point improvement in FFP (95% CI -2.1 to -1.6) during the early period. Frailty by SPPB and FFP did not change in those who were not frail before transplant. Approximately 84% of survivors who were frail before transplant became not frail after transplant. CONCLUSIONS: Pre-operative frailty resolves in many patients after lung transplantation. Because a large proportion of frailty may be attributable to advanced lung disease, frailty alone should not be an absolute contraindication to transplantation.

8.
Clin Transplant ; 33(5): e13515, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30849195

RESUMO

Lymphocytic bronchitis (LB) precedes chronic lung allograft dysfunction. The relationships of LB (classified here as Endobronchial or E-grade rejection) to small airway (A- and B-grade) pathologies are unclear. We hypothesized that gene signatures common to allograft rejection would be present in LB. We studied LB in two partially overlapping lung transplant recipient cohorts: Cohort 1 included large airway brushes (6 LB cases and 18 post-transplant referents). Differential expression using DESeq2 was used for pathway analysis and to define an LB-associated metagene. In Cohort 2, eight biopsies for each pathology subtype were matched with pathology-free biopsies from the same subject (totaling 48 samples from 24 subjects). These biopsies were analyzed by multiplexed digital counting of immune transcripts. Metagene score differences were compared by paired t tests. Compared to referents in Cohort 1, LB demonstrated upregulation of allograft rejection pathways, and upregulated genes in these cases characterized an LB-associated metagene. We observed statistically increased expression in Cohort 2 for this LB-associated metagene and four other established allograft rejection metagenes in rejection vs paired non-rejection biopsies for both E-grade and A-grade subtypes, but not B-grade pathology. Gene expression-based categorization of allograft rejection may prove useful in monitoring lung allograft health.

9.
Curr Opin Anaesthesiol ; 32(2): 136-143, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30817385

RESUMO

PURPOSE OF REVIEW: Teaching in the stressful, high-acuity environment of the ICU is challenging. The intensivist-educator must use teaching strategies that are both effective and time-efficient, as well as evidence-based approaches to the ICU curriculum. This review provides an overview of pertinent educational theories and their implications on educational practices, a selection of effective teaching techniques, and a review on feedback. RECENT FINDINGS: Evidence supports the role of conceptual frameworks in providing the educator with a key perspective to obtain a deeper understanding of the factors contributing to an effective and goal-directed education in the ICU. The role of simulation training for technical and nontechnical skills acquisition is growing. Feedback is difficult to provide, but critical to facilitate learner success; frameworks, and approaches are becoming more standardized. SUMMARY: Direct teaching should be goal-oriented, sequential, and adjusted to the level of the learner. The ICU curriculum should optimize cognitive load, reduce stress that is unrelated to the activity, include resilience training, and help trainees deal with stressful clinical situations better. Simulation is a powerful tool to promote technical and nontechnical skills. Providing feedback is essential and a skill that can be taught and enhanced with structure, prompts, and tools.


Assuntos
Anestesiologia/educação , Medicina Baseada em Evidências/educação , Unidades de Terapia Intensiva/organização & administração , Internato e Residência/organização & administração , Ensino , Anestesiologistas/organização & administração , Anestesiologistas/psicologia , Competência Clínica , Currículo , Eficiência Organizacional , Metas , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Estresse Ocupacional/prevenção & controle , Estresse Ocupacional/psicologia , Resiliência Psicológica , Treinamento por Simulação/organização & administração , Treinamento por Simulação/tendências
10.
Transpl Infect Dis ; 21(3): e13084, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30924986

RESUMO

BACKGROUND: Preoperative Mycobacterium abscessus infection is often considered a contraindication to lung transplantation because of its association with poor outcomes after transplant. Detailed strategies for bridging to transplant, post-operative management, and data regarding outcomes are lacking. METHODS: We reviewed outcomes in subjects with M abscessus infection who underwent lung transplantation between 2010 and 2018 at the University of California San Francisco. M abscessus infection was defined by American Thoracic Society (ATS) criteria. Data collected included age, FEV1 , BMI, LAS, antibiotic regimens, and other management decisions. Time to chronic lung allograft dysfunction (CLAD) and survival were also assessed. RESULTS: Of 387 lung transplant recipients, seven were infected with M abscessus at the time of listing. All received multiple antibiotics before transplant. While all subjects converted to smear negative for acid-fast bacilli before listing, five of the seven remained culture-positive at the time of transplant. After transplant, subjects received a median of 6 months of a multi-antibiotic regimen. One subject developed a post-operative M abscessus soft tissue infection that was treated medically. Six of the seven subjects survived the observation period; one died unrelated to M abscessus. Time to CLAD and survival were similar to a contemporary comparator group of CF transplant recipients. CONCLUSION: Lung transplant recipients with M abscessus infection have a low incidence of recurrent infection, excellent survival, and freedom from CLAD when an aggressive management and surveillance strategy is utilized. Given these findings, M abscessus infection may not be considered a contraindication to lung transplantation.


Assuntos
Gerenciamento Clínico , Transplante de Pulmão , Infecções por Micobactéria não Tuberculosa/tratamento farmacológico , Adolescente , Adulto , Antibacterianos/uso terapêutico , Contraindicações , Fibrose Cística/complicações , Feminino , Humanos , Pulmão/microbiologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Mycobacterium abscessus , Recidiva , Adulto Jovem
11.
Artigo em Inglês | MEDLINE | ID: mdl-30747726

RESUMO

PURPOSE OF REVIEW: Teaching in the stressful, high-acuity environment of the ICU is challenging. The intensivist-educator must use teaching strategies that are both effective and time-efficient, as well as evidence-based approaches to the ICU curriculum. This review provides an overview of pertinent educational theories and their implications on educational practices, a selection of effective teaching techniques, and a review on feedback. RECENT FINDINGS: Evidence supports the role of conceptual frameworks in providing the educator with a key perspective to obtain a deeper understanding of the factors contributing to an effective and goal-directed education in the ICU. The role of simulation training for technical and nontechnical skills acquisition is growing. Feedback is difficult to provide, but critical to facilitate learner success; frameworks, and approaches are becoming more standardized. SUMMARY: Direct teaching should be goal-oriented, sequential, and adjusted to the level of the learner. The ICU curriculum should optimize cognitive load, reduce stress that is unrelated to the activity, include resilience training, and help trainees deal with stressful clinical situations better. Simulation is a powerful tool to promote technical and nontechnical skills. Providing feedback is essential and a skill that can be taught and enhanced with structure, prompts, and tools.

12.
Histopathology ; 74(2): 341-349, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30152895

RESUMO

AIMS: The objective of this study was to quantify the impact of pirfenidone or nintedanib treatment on lung histopathology and molecular mediators of fibrosis in patients with idiopathic pulmonary fibrosis (IPF). METHODS AND RESULTS: We collected lung tissue from IPF patients at the time of lung transplantation. Histopathological changes were quantified using a blinded scoring method. Proteins associated with senescence or active TGF-ß were quantified in lung tissues by immunoblot and immunostaining. Histopathological quantification showed similar amounts of dense collagen fibrosis, fibroblast foci and alveolar macrophages in untreated or pirfenidone- or nintedanib-treated IPF patients. There was less diffuse alveolar damage and organising pneumonia in pirfenidone-treated IPF patients. Lungs of nintedanib-treated patients had a trend towards less lymphocytic interstitial infiltration. There was no difference in expression of p-SMAD3, p21 or p16 in the lungs of untreated, pirfenidone- or nintedanib-treated IPF patients. Alveolar epithelial cells, but not fibroblast foci, were immunoreactive to p16. Pirfenidone or nintedanib treatment did not inhibit activation of senescence programming in cultured lung epithelial cells mediated by hydrogen peroxide. CONCLUSION: Pirfenidone and nintedanib do not modulate expression of senescence markers, levels of p-SMAD3 or the amount of fibrosis in IPF lungs. Treated patients have less histopathological evidence of acute lung injury at the time of lung transplantation.


Assuntos
Células Epiteliais Alveolares/patologia , Fibrose Pulmonar Idiopática/patologia , Indóis/farmacologia , Pulmão/patologia , Piridonas/farmacologia , Idoso , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Linhagem Celular Tumoral , Feminino , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Indóis/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Piridonas/uso terapêutico
13.
Transplantation ; 103(3): 493-501, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30211828

RESUMO

BACKGROUND: Cytomegalovirus (CMV) infection is a risk factor for chronic lung allograft dysfunction (CLAD), which limits survival in lung allograft recipients. Natural killer (NK) cells that express the NKG2C receptor mediate CMV-specific immune responses. We hypothesized that NKG2C NK cells responding to CMV in the lung allograft would reduce CMV-related inflammation and would improve CLAD-free survival. METHODS: We prospectively followed 130 subjects who underwent lung transplantation from 2012 to 2016. Bronchoalveolar lavage (BAL) NK cells were immunophenotyped for NKG2C, maturation, and proliferation markers. CMV viral load, serologies, serial spirometry, and mortality were recorded from medical records. Natural killer cell subset association with CMV endpoints were made using generalized estimating equation-adjusted linear models. BAL NKG2C NK cell association with CLAD-free survival was assessed by Cox proportional hazards modeling. RESULTS: NKG2C NK cells were more mature and proliferative than NKG2C NK cells and represented a median of 7.8% of BAL NK cells. The NKG2C NK cell proportion increased prior to the first detection of viremia and was nearly tripled in subjects with high level viremia (>1000 copies/mL) compared with no detected viremia. Subjects with increased BAL NKG2C NK cells, relative to the median, had a significantly increased risk for CLAD or death (hazard ratio, 4.2; 95% confidence interval, 1.2-13.3). CONCLUSIONS: The BAL NKG2C NK cell proportion may be a relevant biomarker for assessing risk of CMV viremia and quantifying potential CMV-related graft injury that can lead to CLAD or death.


Assuntos
Lavagem Broncoalveolar , Infecções por Citomegalovirus/imunologia , Transplante de Pulmão , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Viremia/imunologia , Adulto , Idoso , Biomarcadores , Proliferação de Células , Citomegalovirus , Intervalo Livre de Doença , Feminino , Humanos , Imunofenotipagem , Inflamação , Células Matadoras Naturais/metabolismo , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Fenótipo , Modelos de Riscos Proporcionais , Estudos Prospectivos , Espirometria , Transplante Homólogo , Resultado do Tratamento
14.
Am J Respir Crit Care Med ; 199(8): 1008-1019, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30303408

RESUMO

RATIONALE: Although lung transplantation aims to improve health-related quality of life (HRQL), existing instruments fail to include health domains considered important in this population. OBJECTIVES: We aimed to develop a comprehensive lung transplant-specific instrument to address this shortcoming. METHODS: We developed a pool of 126 candidate items addressing domains previously identified as important by lung transplant recipients. Through cognitive interviews conducted in 43 transplant recipients, items deemed irrelevant or redundant were dropped. The 84 remaining items were field tested in lung transplant recipients. Exploratory and confirmatory factor analyses were used to evaluate the factor structure, and scales were evaluated for internal consistency and construct validity. MEASUREMENTS AND MAIN RESULTS: The 84-item preliminary survey was administered to 201 lung transplant recipients with a mean age of 57.9 (±12.7) years; 46% were female. After factor analyses and internal consistency evaluation, we retained 60 items comprising the Lung Transplant Quality of Life (LT-QOL) Survey. The LT-QOL contains 10 scales that measure symptoms, health perceptions, functioning, and well-being. The confirmatory factor analysis model had good approximate fit (comparative fit index = 0.990; standardized root-mean-square residual = 0.062). Cronbach αs for the 10 scales ranged from 0.75 to 0.95. Interscale correlations were consistent with hypothesized relationships. Subjects with severe chronic lung allograft dysfunction (n = 13) reported significantly worse HRQL than subjects without chronic lung allograft dysfunction (n = 168) on 6 of the 10 LT-QOL scales. CONCLUSIONS: The LT-QOL is a new, multidimensional instrument that characterizes and quantifies HRQL in lung transplant recipients.


Assuntos
Transplante de Pulmão , Qualidade de Vida , Adulto , Idoso , Feminino , Humanos , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/psicologia , Transplante de Pulmão/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida/psicologia , Reprodutibilidade dos Testes , Inquéritos e Questionários , Adulto Jovem
15.
Chest ; 154(4): e89-e92, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30290953

RESUMO

Idiopathic pulmonary fibrosis is the most common idiopathic interstitial pneumonia. Prognosis is poor with a median survival <3 years. Pirfenidone is one of two US Food and Drug Administration-approved medications that slow disease progression. We describe the development of lymphadenopathy or a sarcoid-like reaction following initiation of pirfenidone, a complication not previously reported.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Piridonas/efeitos adversos , Sarcoidose Pulmonar/induzido quimicamente , Humanos , Fibrose Pulmonar Idiopática/cirurgia , Transplante de Pulmão , Doenças Linfáticas/induzido quimicamente , Masculino , Pessoa de Meia-Idade
16.
Thorac Cardiovasc Surg Rep ; 7(1): e27-e29, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29977735

RESUMO

Background Pulmonary mucormycosis is a rare fungal infection that carries a high mortality. Given the rarity of this disease, its management has not been well established. Case Description We report a 36-year-old female presenting with right middle and lower lobe pulmonary mucormycosis during the third trimester of pregnancy. Diagnosis was established using chest computed tomography followed by bronchoalveolar lavage and lung biopsy. Prompt initiation of amphotericin B and right middle and lower lobe lobectomy resulted in maternal survival and fetal viability. Conclusion This favorable outcome is attributed to extensive communication between treatment teams in addition to comprehensive surgical planning.

17.
Clin Transplant ; 32(8): e13332, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29920787

RESUMO

Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C0 /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1 ± 1.6 days for CYP3A extensive metabolizers (EM, P < 0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2 ± 0.5 days less (P = 0.01) and EM spent 2.1 ± 0.5 days less (P < 0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C0 /D (P < 0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, P = 0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, P = 0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.


Assuntos
Citocromo P-450 CYP3A/genética , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/genética , Imunossupressores/administração & dosagem , Transplante de Pulmão/métodos , Polimorfismo de Nucleotídeo Único , Tacrolimo/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Transplantados
18.
Clin Transplant ; 32(6): e13274, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29742287

RESUMO

BACKGROUND: Frailty is prevalent in lung transplant candidates (LTC) and is associated with waitlist delisting or death. We performed a pilot study to assess the safety and feasibility of a home-based, mobile health technology-facilitated intervention to treat frailty in LTC. METHODS: We performed an 8-week, nonrandomized, home-based exercise and nutrition intervention in LTC with Short Physical Performance Battery (SPPB) frailty scores of ≤11. The intervention utilized a customized, mobile device application ("app") enabling monitoring and progression of the intervention in real time. We aimed to evaluate key process measures. Secondarily, we tested whether the intervention could improve frailty scores quantified by the SPPB and Fried Frailty Phenotype (FFP). RESULTS: A total of 15 subjects enrolled were 63 ± 5.7 years old; oxygen requirements ranged from 3 to 15LPM. Thirteen subjects completed the intervention. Over 108 subject-weeks, there were no adverse events. Subjects found the app engaging and easy to work with. SPPB frailty improved in 7 (54%) and FFP improved in 8 (62%). There was a strong trend toward improved frailty scores (SPPB change 1.0 ± 1.9; P = .08; FFP change -0.6 ± 1.0; P = .07). CONCLUSION: In this pilot study, we found that a home-based prehabilitation program that leverages mobile health technology to target frailty in LTC is well received, safe, and capable of improving physical frailty scores.


Assuntos
Terapia por Exercício , Fragilidade/reabilitação , Serviços de Assistência Domiciliar/estatística & dados numéricos , Transplante de Pulmão , Estado Nutricional , Telemedicina/métodos , Adulto , Intervenção Médica Precoce , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Aplicativos Móveis , Projetos Piloto , Prognóstico
19.
Am J Transplant ; 18(8): 2043-2049, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29673076

RESUMO

Lung transplant immunosuppression regimens generally include the calcineurin inhibitor tacrolimus. We hypothesized that mean residual expression (MRE) of calcineurin-dependent genes assesses rejection and infection risk better than does tacrolimus trough. We prospectively followed 44 lung allograft recipients at 2 to 18 months posttransplant and measured changes in whole blood interleukin-2, interferon-γ, and granulocyte-macrophage colony-stimulating factor gene expression following a tacrolimus dose. Posttransplant duration, immunosuppressive medication levels, and bronchoscopic rejection and infection assessments were compared with MRE by using generalized-estimating equation-adjusted models. Prednisolone effect on MRE was assessed ex vivo in blood samples from nontransplanted controls. Tacrolimus concentration inhibiting 50% of cytokine production (IC50 ) was measured in a pretransplant subset. Results showed that MRE did not change with diagnosis of rejection but that airway infection was associated with a 20% absolute decrease (95% confidence interval 11%-29%). MRE increased with time after transplant but was not associated with tacrolimus trough. Interestingly, MRE correlated inversely with corticosteroid dose in the study cohort and ex vivo. Pretransplant tacrolimus IC50 depended on the cytokine measured and varied between individuals, suggesting a range in baseline responses to tacrolimus. We conclude that MRE identifies infection risk in lung allograft recipients, potentially integrating calcineurin inhibitor and steroid effects on lymphocyte effector function.


Assuntos
Biomarcadores/análise , Calcineurina/metabolismo , Rejeição de Enxerto/diagnóstico , Imunossupressão , Transplante de Pulmão/efeitos adversos , Aloenxertos , Anti-Inflamatórios/administração & dosagem , Inibidores de Calcineurina/administração & dosagem , Estudos de Casos e Controles , Feminino , Seguimentos , Perfilação da Expressão Gênica , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/genética , Sobrevivência de Enxerto , Humanos , Imunossupressores/administração & dosagem , /genética , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prednisolona/administração & dosagem , Prognóstico , Estudos Prospectivos , Fatores de Risco , Tacrolimo/administração & dosagem
20.
Am J Transplant ; 18(8): 1995-2004, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29667786

RESUMO

Frailty is associated with increased mortality among lung transplant candidates. We sought to determine the association between frailty, as measured by the Short Physical Performance Battery (SPPB), and mortality after lung transplantation. In a multicenter prospective cohort study of adults who underwent lung transplantation, preoperative frailty was assessed with the SPPB (n = 318) and, in a secondary analysis, the Fried Frailty Phenotype (FFP; n = 299). We tested the association between preoperative frailty and mortality following lung transplantation with propensity score-adjusted Cox models. We calculated postestimation marginalized standardized risks for 1-year mortality by frailty status using multivariate logistic regression. SPPB frailty was associated with an increased risk of both 1- and 4-year mortality (adjusted hazard ratio [aHR]: 7.5; 95% confidence interval [CI]: 1.6-36.0 and aHR 3.8; 95%CI: 1.8-8.0, respectively). Each 1-point worsening in SPPB was associated with a 20% increased risk of death (aHR: 1.20; 95%CI: 1.08-1.33). Frail subjects had an absolute increased risk of death within the first year after transplantation of 12.2% (95%CI: 3.1%-21%). In secondary analyses, FFP frailty was associated with increased risk of death within the first postoperative year (aHR: 3.8; 95%CI: 1.1-13.2) but not over longer follow-up. Preoperative frailty is associated with an increased risk of death after lung transplantation.


Assuntos
Fragilidade/mortalidade , Pneumopatias/mortalidade , Transplante de Pulmão/mortalidade , Complicações Pós-Operatórias , Qualidade de Vida , Índice de Gravidade de Doença , Idoso , Feminino , Seguimentos , Fragilidade/diagnóstico , Humanos , Pneumopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida
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