Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 148
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PLoS One ; 15(3): e0229445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160239

RESUMO

The Wnt/ß-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of ß-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the Wnt/ß-catenin signaling, has not been described. A specific interventional strategy targeting this pathway for fibrosis remains to be defined. We developed monoclonal antibodies against members of the RSPO family (RSPO1, 2, and 3) and probed their potential function in fibrosis in vivo. We demonstrated that RSPO3 plays a critical role in the development of fibrosis in multiple organs. Specifically, an anti-RSPO3 antibody, OMP-131R10, when dosed therapeutically, attenuated fibrosis in carbon tetrachloride (CCl4)-induced liver fibrosis, bleomycin-induced pulmonary and skin fibrosis models. Mechanistically, we showed that RSPO3 induces multiple pro-fibrotic chemokines and cytokines in Kupffer cells and hepatocytes. We found that the anti-fibrotic activity of OMP-131R10 is associated with its inhibition of ß-catenin activation in vivo. Finally, RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in mouse models of fibrosis and in patients with idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Together these data provide an anti-fibrotic strategy for targeting the Wnt/ß-catenin pathway through RSPO3 blockade and support that OMP-131R10 could be an important therapeutic agent for fibrosis.

2.
Eur Respir J ; 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32139456

RESUMO

INTRODUCTION: Sarcoidosis associated pulmonary hypertension (SAPH) is associated with reduced survival in single center studies. An international registry for SAPH (ReSAPH) with long-term follow-up was established to enrich our knowledge of this complication of sarcoidosis. This analysis aims to elucidate factors associated with reduced transplant-free survival in SAPH patients. METHODS: ReSAPH contains prospectively collected outcomes of SAPH patients since the time of registry enrollment. Information analyzed includes right heart catheterization data, pulmonary function testing, chest x-ray Scadding stage, six minute walk distance (6MWD) among others. Cox regression models were used to identify independent predictors of transplant-free survival. RESULTS: Data from a total of 215 patients followed for a mean of 2.5±1.9 years were available for analysis. In the 159 pre-capillary patients, the KM adjusted 1, 3 and 5 year transplant free survival was 89.2%, 71.7% and 62.0%, respectively. In the incident and prevalent groups, KM adjusted 1, 3 and 5 year transplant free survival was 83.5%, 70.3% and 58.3% and 94.7%, 72.2%, and 66.3% respectively. Patients with reduced DLCO (<35% predicted) and 6MWD <300 m in the pre-capillary cohort had significantly worse transplant-free survival. Reduced 6MWD and preserved FEV1/FVC ratio were identified as independent risk factors for reduced transplant-free survival in the pre-capillary cohort. CONCLUSION: Reduced diffusion capacity (<35% of predicted) and 6MWD <300 m at the time of registry enrollment were associated with reduced transplant-free survival in the overall precapillary cohort. Preserved FEV1/FVC ratio was also identified as an independent risk factor for worsened outcomes.

4.
Adv Ther ; 36(10): 2927-2929, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31502216

RESUMO

In the Original Publication the colors of Figure 2 have been switched. The correct figures are given below.

5.
Transpl Infect Dis ; 21(6): e13166, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31487755

RESUMO

BACKGROUND: Cytomegalovirus (CMV) infection is common in thoracic organ transplant recipients. Valganciclovir and ganciclovir are used for both prophylaxis and treatment of this infection, but intolerance and treatment failure are common. Letermovir has been demonstrated to reduce the risk of CMV infection when used for prophylaxis in allogeneic hematopoietic cell transplantation. However, there are no data on its efficacy in thoracic organ transplantation. METHODS: We examined the use of letermovir for either CMV prophylaxis (primary and secondary) or treatment in heart and lung transplant recipients at our institution from February 1, 2018, through December 31, 2018. RESULTS: Nine total patients received letermovir at our institution (8 lung transplant, 1 heart transplant) during the study period. Letermovir was prescribed for CMV prophylaxis in eight patients (primary prophylaxis in two patients and secondary prophylaxis in 6 patients), and for treatment of CMV DNAemia in two cases. One patient received letermovir for both secondary prophylaxis and treatment on separate occasions. Three out of 8 (37.5%) patients receiving letermovir for prophylaxis developed CMV DNAemia during prophylaxis. One patient treated for CMV disease had clinical failure with a sharp rise in serum CMV DNA PCR. The other patient treated for low-grade CMV DNAemia initially had a slight rise in CMV DNA PCR, but has since had a sustained response. No major side effects were experienced, and 2 patients reported minor side effects. CONCLUSION: Letermovir was well tolerated with only minor side effects reported; however, the rate of development of CMV DNAemia on prophylaxis was considerable. Further study of the dosing and efficacy of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients is warranted.

6.
Lancet Respir Med ; 7(9): 780-790, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31416769

RESUMO

BACKGROUND: Idiopathic interstitial pneumonias are often complicated by pulmonary hypertension, increasing morbidity and mortality. There are no approved treatments for pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP). We aimed to evaluate the efficacy and safety of riociguat in patients with PH-IIP. METHODS: RISE-IIP was a double-blind, randomised, placebo-controlled study done at 65 pulmonary hypertension and interstitial lung disease centres in 19 countries to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Eligible patients were adults (aged 18-80 years) diagnosed with idiopathic interstitial pneumonia (as per American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines), forced vital capacity (FVC) of at least 45%, 6MWD of 150-450 m, WHO functional classes II-IV, precapillary pulmonary hypertension confirmed by right heart catheterisation, systolic blood pressure of at least 95 mm Hg, and no signs or symptoms of hypotension. Patients were randomly allocated (1:1) using an interactive voice and web response system to riociguat (0·5-2·5 mg three times daily) or placebo for 26 weeks (main study), after which they could enter an open-label extension in which all patients received riociguat. The primary endpoint was change in 6-min walking distance (6MWD) in the intention-to-treat population. Prespecified safety variables included adverse events and serious adverse events, laboratory parameters, and adverse events of special interest (haemoptysis and symptomatic hypotension), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02138825. FINDINGS: Between June 4, 2014, and May 5, 2016, we enrolled 229 participants. After the exclusion of 82 participants, 147 were randomly allocated to treatment (73 to riociguat, 74 to placebo). The study was terminated early (median treatment duration 157 days [range 6-203]) at the request of the data monitoring committee owing to increased serious adverse events (main study: 27 [37%] of 73 participants in the riociguat group vs 17 [23%] of 74 in the placebo group) and mortality in patients receiving riociguat, and the absence of efficacy signals in the riociguat group. 11 patients died in the main study (eight in the riociguat group, three in the placebo group), and nine died in the extension phase (one in the riociguat group, eight in the former placebo group; all received riociguat). In the main study, the most common adverse events were peripheral oedema (16 [22%] of 73 in the riociguat group vs seven [9%] of 74 in the placebo group) and diarrhoea (11 [15%] vs seven [9%]). The most common serious adverse events were worsening of interstitial lung disease (main study: six [8%] of 73 in the riociguat group vs five [7%] of 74 in the placebo group) and pneumonia (four [5%] vs one [1%]). Riociguat did not improve 6MWD versus placebo at 26 weeks (least-squares mean difference 21 m; 95% CI -9 to 52). INTERPRETATION: In patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavourable risk-benefit profile. Riociguat should not be used in patients with PH-IIP. FUNDING: Bayer AG and Merck & Co.

7.
Ther Adv Respir Dis ; 13: 1753466619868935, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409257

RESUMO

Pulmonary sarcoidosis is the most common form of sarcoidosis, accounting for the initial presentation in over 70% patients and with eventual presence in 90% of patients with sarcoidosis. However, the course of the disease is often unpredictable; its manifestations can be highly variable and its treatment may not be effective in all patients. As such, the optimized treatment of pulmonary sarcoidosis often requires a thoughtful personalized approach with the need to get the patient involved in decisions of management. In many patients with pulmonary sarcoidosis, the disease is self-limited and nonprogressive, thus treatment is not necessary. In other patients, the presence of significant symptoms or functional limitation often associated with worsening radiological changes and pulmonary function tests warrants treatment. Corticosteroids are the first-line treatment for pulmonary sarcoidosis; antimetabolites are second-line agents, with methotrexate being most commonly employed. Antitumor necrosis alpha antibodies, especially infliximab, are emerging as potential third-line agents. A high index of suspicion should be held for pulmonary hypertension and other comorbidities that may complicate the course of patients with advanced sarcoidosis. Lung transplantation may be the only option for patients who have refractory disease despite maximal medical therapy.

8.
Curr Opin Pulm Med ; 25(5): 459-467, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31365380

RESUMO

PURPOSE OF REVIEW: Pulmonary hypertension has been reported to complicate the course of a number of fibrotic lung diseases, including idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis and nonspecific interstitial pneumonitis. Most commonly, mild elevations in the mean pulmonary artery pressure are seen in patients with advanced pulmonary fibrosis. However, some patients may develop severe pulmonary hypertension, which appears out of proportion to the degree of their restrictive lung disease. RECENT FINDINGS: The benefits of pulmonary vasodilator therapy have yet to be established in pulmonary hypertension complicating fibrotic lung disease. In fact, one recent clinical trial examining riociguat in patients with pulmonary hypertension complicating idiopathic interstitial pneumonias was terminated early for an increased risk of death or hospitalization. Multiple clinical trials on this topic are currently ongoing, including studies examining inhaled pulmonary vasodilator therapies. SUMMARY: The development of pulmonary hypertension is associated with increased exertional oxygen requirements, worsened functional capacity and attenuated life expectancy. It is hoped that continued research will find an effective therapy for this condition, which will improve quality of life and extend life expectancy in patients with this condition.

9.
Adv Ther ; 36(10): 2910-2926, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401786

RESUMO

INTRODUCTION: This study assessed baseline cardiovascular (CV) risk factors, concomitant CV medication use, risk of major adverse cardiac events-plus (MACE-plus), and bleeding adverse events (AEs) in patients with idiopathic pulmonary fibrosis (IPF) in three randomized, placebo-controlled phase III trials of pirfenidone. METHODS: Patients in the pirfenidone phase III trials were included. Patients with unstable or deteriorating cardiac disease within 6 months before enrollment were ineligible. Medical history at baseline and concomitant CV medication use during treatment were reported. A retrospective, blinded review of AE preferred terms was conducted to identify MACE-plus and bleeding events. Subgroup analyses examined the impact of concomitant CV medication use on how pirfenidone treatment affected clinical outcomes. RESULTS: In total, 1247 patients were included [n = 623 pirfenidone (2403 mg/day) and n = 624 placebo]. The median age was 68 years, 74% were male, and 65% were current/former smokers. Commonly reported CV risk factors included hypertension (52%), obesity (44%), hypercholesterolemia (23%), and hyperlipidemia (23%). Pre-existing cardiac disorders included coronary artery disease (16%), myocardial infarction (5%), and atrial fibrillation (5%). Lipid-modifying agents (60%), antithrombotic agents (54%), and renin-angiotensin inhibitors (39%) were commonly used concomitant CV medications. The incidences of MACE-plus and bleeding events were similar between the pirfenidone and placebo groups (1.8% and 2.9% for MACE-plus events and 3.7% and 4.3% for bleeding events, respectively). Except for patients receiving heparin, pirfenidone had a beneficial effect compared with placebo on efficacy outcomes regardless of concomitant CV medications. CONCLUSIONS: CV risk factors and comorbidities and use of concomitant CV medications are common in patients with IPF. Pirfenidone did not appear to increase the risk of CV or bleeding events. Use of several concomitant CV medications, including warfarin, did not appear to adversely impact pirfenidone's beneficial effect on efficacy outcomes. TRIAL REGISTRATION: NCT00287716, NCT00287729, and NCT01366209. FUNDING: F. Hoffmann-La Roche Ltd. and Genentech, Inc.

11.
Clin Respir J ; 13(9): 567-573, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301257

RESUMO

INTRODUCTION AND OBJECTIVE: Pulmonary hypertension (PH) complicating idiopathic pulmonary fibrosis (IPF) is challenging to diagnose given inaccuracy of transthoracic echocardiogram (TTE) measurements. However, it has significant prognostic implications and is therefore important to accurately identify. METHODS: We conducted a cross-sectional study of patients with IPF who underwent RHC as part of their evaluation. A variety of commonly available noninvasive variables were evaluated for their ability to predict pulmonary arterial pressure in a linear regression model, including the traditionally used right ventricular systolic pressure (RVSP) estimated from TTE. RESULTS: There were 105 eligible patients identified from January 2006 to July 2016. The average age was 62.7 ± 7.7 years, 35 had RHC proven PH and 43% ultimately underwent lung transplantation. A linear model including three terms: RVSP (ANOVA P < .01), the ratio of FVC/DLCO from PFTs (P = .05) and pulmonary artery to aorta diameter ratio from CT (P < .01) was found to predict the mean pulmonary artery pressure more reliably than RVSP alone (R2 .39 vs .29, P < .05), with a lower rate of incorrect classification of PH status in these individuals (27.6 vs 35.2%, P = .05) and high negative predictive value (87.2%). CONCLUSION: If used in conjunction with RVSP from TTE, parameters from PFTs and the CT scan more accurately predict the presence or absence of PH than any of the variables in isolation. Using these in concert may allow greater discrimination in deciding which patients to subject to diagnostic right heart catheterization.


Assuntos
Pressão Sanguínea/fisiologia , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/diagnóstico por imagem , Fibrose Pulmonar Idiopática/etiologia , Idoso , Aorta/anatomia & histologia , Aorta/diagnóstico por imagem , Cateterismo Cardíaco/métodos , Estudos Transversais , Ecocardiografia/métodos , Humanos , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/cirurgia , Fibrose Pulmonar Idiopática/fisiopatologia , Transplante de Pulmão/métodos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Artéria Pulmonar/anatomia & histologia , Artéria Pulmonar/diagnóstico por imagem , Testes de Função Respiratória/métodos , Tomografia Computadorizada por Raios X/métodos , Função Ventricular Direita/fisiologia
12.
Respir Med ; 154: 1-5, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31176795

RESUMO

BACKGROUND: The impact of hospitalization on patient outcomes is increasingly recognized and considered in the prognostication of many pulmonary disorders. We sought to evaluate the impact of hospitalization on survival in connective tissue disease-interstitial lung disease (CTD-ILD) patients. METHODS: A chart review of patients with CTD-ILD followed at a tertiary care center was performed. Patients were stratified into two groups based on hospitalization status. Outcomes of the groups were compared using Kaplan-Meier survival analyses as well as multivariate competing risk analysis. RESULTS: There were 137 patients identified with confirmed CTD-ILD. Patients who underwent hospitalization for any reason had a significant decrease in transplant-free survival compared to the never hospitalized cohort (3-year survival 60% vs. 94%; p = 0.0001). Hospitalization for ≥7 days was associated with worse outcomes than those hospitalized for <7 days (median survival 1.59 years vs. 7.17 years, p = 0.0012). Based on multivariate competing risk analysis, factors associated with death, with lung transplantation as a competing risk, were age (HR = 1.05 [95% 1.01-1.09]; P = 0.0443), male gender (HR = 4.94 [95% CI: 1.58-15.41]; P = 0.006), and all cause hospitalization (HR = 11.97 [95% CI: 1.36-105.49]; P = 0.0253). CONCLUSION: This study highlights the impact of hospitalization on subsequent outcomes in the CTD-ILD population with a significantly reduced transplant-free survival demonstrated, especially after cardiopulmonary hospitalization events.

13.
Respir Med ; 153: 44-51, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31153107

RESUMO

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) demonstrate a range of lung function impairment. However, the efficacy of antifibrotics compared with placebo has not been assessed in patients with more advanced disease. This post-hoc analysis investigated the efficacy and safety of pirfenidone versus placebo in patients with IPF and more advanced lung function impairment, defined as percent predicted forced vital capacity (%FVC) < 50% and/or percent predicted carbon monoxide diffusing capacity <35%. METHODS: Patients randomised to pirfenidone 2,403 mg/day or placebo in the ASCEND (NCT01366209) and CAPACITY (NCT00287716; NCT00287729) trials with more advanced baseline lung function impairment (pirfenidone, n = 90; placebo, n = 80) were included. Mortality, lung function, hospitalisation, exercise capacity and dyspnoea were investigated over 52 weeks. RESULTS: At Week 52 versus placebo, pirfenidone was associated with significantly lower risks of all-cause mortality (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.09-0.86; p=0.0180), ≥10% absolute %FVC decline or all-cause mortality (HR 0.40; 95% CI 0.23-0.69; p=0.0006) and ≥10% absolute %FVC decline or respiratory-related hospitalisation or all-cause mortality (HR 0.46; 95% CI 0.28-0.76; p=0.0018). At Week 52, median treatment differences favouring pirfenidone were 36.7 m for 6-min walk distance and -8.0 points for the University of California-San Diego Shortness of Breath Questionnaire total score. Treatment-emergent adverse events (TEAEs) led to discontinuation in 14.4% and 21.3% of patients with pirfenidone and placebo, respectively. CONCLUSION: Pirfenidone demonstrated clinically relevant benefits across multiple domains in patients with IPF and more advanced disease without an increased risk of discontinuation due to TEAEs. CLINICAL TRIALS REGISTRATION: clinicaltrials. gov (ASCEND: NCT01366209; CAPACITY: NCT00287716; NCT00287729).

14.
Curr Opin Pulm Med ; 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31219836

RESUMO

PURPOSE OF REVIEW: Pulmonary hypertension has been reported to complicate the course of a number of fibrotic lung diseases, including idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis and nonspecific interstitial pneumonitis. Most commonly, mild elevations in the mean pulmonary artery pressure are seen in patients with advanced pulmonary fibrosis. However, some patients may develop severe pulmonary hypertension, which appears out of proportion to the degree of their restrictive lung disease. RECENT FINDINGS: The benefits of pulmonary vasodilator therapy have yet to be established in pulmonary hypertension complicating fibrotic lung disease. In fact, one recent clinical trial examining riociguat in patients with pulmonary hypertension complicating idiopathic interstitial pneumonias was terminated early for an increased risk of death or hospitalization. Multiple clinical trials on this topic are currently ongoing, including studies examining inhaled pulmonary vasodilator therapies. SUMMARY: The development of pulmonary hypertension is associated with increased exertional oxygen requirements, worsened functional capacity and attenuated life expectancy. It is hoped that continued research will find an effective therapy for this condition, which will improve quality of life and extend life expectancy in patients with this condition.

15.
Lancet Respir Med ; 7(6): 487-496, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30948346

RESUMO

BACKGROUND: In the appropriate clinical setting, the diagnosis of idiopathic pulmonary fibrosis (IPF) requires a pattern of usual interstitial pneumonia to be present on high-resolution chest CT (HRCT) or surgical lung biopsy. A molecular usual interstitial pneumonia signature can be identified by a machine learning algorithm in less-invasive transbronchial lung biopsy samples. We report prospective findings for the clinical validity and utility of this molecular test. METHODS: We prospectively recruited 237 patients for this study from those enrolled in the Bronchial Sample Collection for a Novel Genomic Test (BRAVE) study in 29 US and European sites. Patients were undergoing evaluation for interstitial lung disease and had had samples obtained by clinically indicated surgical or transbronchial biopsy or cryobiopsy for pathology. Histopathological diagnoses were made by experienced pathologists. Available HRCT scans were reviewed centrally. Three to five transbronchial lung biopsy samples were collected from all patients specifically for this study, pooled by patient, and extracted for transcriptomic sequencing. After exclusions, diagnostic histopathology and RNA sequence data from 90 patients were used to train a machine learning algorithm (Envisia Genomic Classifier, Veracyte, San Francisco, CA, USA) to identify a usual interstitial pneumonia pattern. The primary study endpoint was validation of the classifier in 49 patients by comparison with diagnostic histopathology. To assess clinical utility, we compared the agreement and confidence level of diagnosis made by central multidisciplinary teams based on anonymised clinical information and radiology results plus either molecular classifier or histopathology results. FINDINGS: The classifier identified usual interstitial pneumonia in transbronchial lung biopsy samples from 49 patients with 88% specificity (95% CI 70-98) and 70% sensitivity (47-87). Among 42 of these patients who had possible or inconsistent usual interstitial pneumonia on HRCT, the classifier showed 81% positive predictive value (95% CI 54-96) for underlying biopsy-proven usual interstitial pneumonia. In the clinical utility analysis, we found 86% agreement (95% CI 78-92) between clinical diagnoses using classifier results and those using histopathology data. Diagnostic confidence was improved by the molecular classifier results compared with histopathology results in 18 with IPF diagnoses (proportion of diagnoses that were confident or provisional with high confidence 89% vs 56%, p=0·0339) and in all 48 patients with non-diagnostic pathology or non-classifiable fibrosis histopathology (63% vs 42%, p=0·0412). INTERPRETATION: The molecular test provided an objective method to aid clinicians and multidisciplinary teams in ascertaining a diagnosis of IPF, particularly for patients without a clear radiological diagnosis, in samples that can be obtained by a less invasive method. Further prospective clinical validation and utility studies are planned. FUNDING: Veracyte.

16.
J Cardiopulm Rehabil Prev ; 39(2): 118-126, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30624371

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic debilitating illness. The effects of vigorous aerobic exercise training (AET) on heart function in PAH are poorly understood. METHODS: Eighteen women with PAH (aged 56.2 ± 8.8 yr, body mass index: 28.8 ± 7.3 kg/m) underwent 10 wk of vigorous AET. Cardiac function was observed at rest and peak exercise using bioelectrical impedance cardiography before and after the AET. Cardiac function was observed in a small PAH subset (n = 7) for 10 wk before beginning the AET. A cohort of sedentary women (n = 19) served as healthy controls. RESULTS: Left ventricular ejection fraction (48 ± 9.2 vs 61.5 ± 13.3%, P = .034) and the systemic vascular resistance index (2258 ± 419.1 vs 2939 ± 962.4 dyn·sec/cm·m, P = .008) were lower at supine rest in the baseline PAH group versus the healthy group, as were peak exercise heart rate (140 ± 13.3 vs 170 ± 13.8 beats/min, P < .001) and systemic vascular resistance index (828 ± 141.1 vs 824 ± 300.9 dyn·sec/cm·m, P = .050) after controlling for age and heart rate. Systemic vascular resistance index measured at peak exercise decreased in the PAH group after AET (828 ± 141.1 vs 766 ± 139.6 dyn·sec/cm·m, P = .020). Left ventricular early diastolic filling ratio worsened in the PAH subset prior to AET (95.9 ± 19.4 vs 76.2 ± 18.9%, P = .043) and remained unchanged after AET. CONCLUSION: Vigorous AET was not associated with significant declines in left ventricular systolic or diastolic function in women with PAH. Aerobic exercise training may be beneficial for reducing afterload and may preserve left ventricular diastolic function.

17.
EBioMedicine ; 40: 541-553, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30692045

RESUMO

BACKGROUND: Allograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure. METHODS: This multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis. FINDINGS: avddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%-9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6-19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable. INTERPRETATION: Lung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure. FUND: National Institutes of Health.


Assuntos
Biomarcadores , Ácidos Nucleicos Livres , Rejeição de Enxerto , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/mortalidade , Doadores de Tecidos , Idoso , Aloenxertos , Comorbidade , Feminino , Rejeição de Enxerto/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Análise de Sequência de DNA , Fatores de Tempo , Transplante Homólogo
18.
Chest ; 155(4): 712-719, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30472023

RESUMO

BACKGROUND: Declines in percent predicted FVC (% predicted FVC), declines in 6-min walk distance (6MWD), and respiratory hospitalizations are events associated with disease progression and mortality in idiopathic pulmonary fibrosis. The incidence of multiple events in the same patient over 12 months of pirfenidone treatment is unknown. METHODS: Patients who received pirfenidone 2,403 mg/d (n = 623) or placebo (n = 624) in the ASCEND (study 016; NCT01366209) and CAPACITY (studies 004 and 006; NCT00287716 and NCT00287729) phase III trials were included in this post hoc analysis. Disease progression events were defined as relative decline in % predicted FVC ≥ 10%, absolute decline in 6MWD ≥ 50 m, respiratory hospitalization, or death from any cause. The incidence of disease progression events over 12 months was assessed. RESULTS: The most frequent disease progression events were declines in % predicted FVC (pirfenidone vs placebo; 202 vs 304 events) and declines in 6MWD (pirfenidone vs placebo; 265 vs 348 events). Fewer patients who received pirfenidone had more than one progression event compared with placebo (17.0% vs 30.1%; P < .0001). Death following one or more progression event occurred less frequently in the pirfenidone group than in the placebo group (2.1% vs 6.3%; P = .0002). CONCLUSIONS: Pirfenidone significantly reduced the incidence of multiple progression events and death after a progression event over 12 months of treatment compared with placebo. These findings suggest that continued treatment with pirfenidone confers a benefit despite the occurrence of any single disease progression event. TRIAL REGISTRY: ClinicalTrials.gov; Nos. NCT01366209, NCT00287716, and NCT00287729; URL: www.clinicaltrials.gov.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Piridonas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/administração & dosagem , Causas de Morte/tendências , Progressão da Doença , Relação Dose-Resposta a Droga , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida/tendências , Resultado do Tratamento , Estados Unidos/epidemiologia , Capacidade Vital
19.
Eur Respir J ; 53(1)2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30545980

RESUMO

Pulmonary hypertension (PH) frequently complicates the course of patients with various forms of chronic lung disease (CLD). CLD-associated PH (CLD-PH) is invariably associated with reduced functional ability, impaired quality of life, greater oxygen requirements and an increased risk of mortality. The aetiology of CLD-PH is complex and multifactorial, with differences in the pathogenic sequelae between the diverse forms of CLD. Haemodynamic evaluation of PH severity should be contextualised within the extent of the underlying lung disease, which is best gauged through a combination of physiological and imaging assessment. Who, when, if and how to screen for PH will be addressed in this article, as will the current state of knowledge with regard to the role of treatment with pulmonary vasoactive agents. Although such therapy cannot be endorsed given the current state of findings, future studies in this area are strongly encouraged.

20.
Respiration ; 96(6): 514-524, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30114692

RESUMO

BACKGROUND: Antifibrotics are recommended for the treatment of individuals with idiopathic pulmonary fibrosis (IPF), but treatment use remains at ∼60%. OBJECTIVE: To investigate the views of individuals with IPF and pulmonologists on the diagnosis and management of IPF to understand treatment patterns. METHODS: Interviews and/or online surveys were completed by patients and pulmonologists from Canada, France, Germany, Italy, Spain, and the UK. Responses from physicians were analyzed by time between diagnosis and treatment initiation in the majority of patients with IPF (group A, > 4 months; group B, ≤4 months). Statistical comparisons between physicians were undertaken using z tests, with p < 0.05 considered statistically significant. RESULTS: The physicians in group A saw fewer patients, were less comfortable discussing the IPF prognosis with patients, and had less belief in the benefits of antifibrotic treatments than the physicians in group B. These physicians' attitudes contrasted with those of the patients, who wanted more information about the IPF prognosis and pharmacological treatment options at diagnosis and were more concerned about preventing disease progression than avoiding medication side effects. Differences between countries were found regarding physicians' comfort in discussing the prognosis at diagnosis and access to care. CONCLUSIONS: Several barriers to antifibrotic treatment, principally reflecting the differing views and values of patients and physicians, were identified in this study, suggesting a need for better patient-physician communication about pharmacological therapy for IPF.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Pneumologistas/psicologia , Piridonas/uso terapêutico , Adulto , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/psicologia , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Conduta Expectante
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA