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1.
JAMA ; 325(18): 1841-1851, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33974018

RESUMO

Importance: Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. Objective: To assess the effect of antimicrobial therapy on clinical outcomes. Design, Setting, and Participants: Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020). Interventions: Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if ≥50 kg, n = 126). No placebo was administered in the usual care alone group. Main Outcomes and Measures: The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. Results: Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%). Conclusions and Relevance: Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease. Trial Registration: ClinicalTrials.gov Identifier: NCT02759120.

2.
Chest ; 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33865835

RESUMO

BACKGROUND: The purpose of this analysis is to provide evidence-based and consensus-derived guidance for clinicians to improve individual diagnostic decision-making for hypersensitivity pneumonitis (HP) and decrease diagnostic practice variability. STUDY DESIGN AND METHODS: Approved panelists developed key questions regarding the diagnosis of HP using the PICO (Population, Intervention, Comparator, and Outcome) format. MEDLINE (via PubMed) and the Cochrane Library were systematically searched for relevant literature, which was supplemented by manual searches. References were screened for inclusion and vetted evaluation tools were used to assess the quality of included studies, to extract data, and to grade the level of evidence supporting each recommendation or statement. The quality of the evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Graded recommendations and ungraded consensus-based statements were drafted and voted on using a modified Delphi technique to achieve consensus. RESULTS: The systematic review of the literature based on 14 PICO questions resulted in 14 key action statements: 12 evidence-based, graded recommendations, and 2 ungraded consensus-based statements. All evidence was of very low quality. INTERPRETATION: Diagnosis of HP should employ a patient-centered approach and include a multidisciplinary assessment that incorporates the environmental and occupational exposure history and CT pattern to establish diagnostic confidence prior to considering BAL and/or lung biopsy. Additional research is needed on the performance characteristics and generalizability of exposure assessment tools and traditional and new diagnostic tests in modifying clinical decision-making for HP, particularly among those with a provisional diagnosis.

3.
Chest ; 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33861992

RESUMO

BACKGROUND: The purpose of this analysis is to provide evidence-based and consensus-derived guidance for clinicians to improve individual diagnostic decision-making for hypersensitivity pneumonitis (HP) and decrease diagnostic practice variability. STUDY DESIGN AND METHODS: Approved panelists developed key questions regarding the diagnosis of HP using the PICO (Population, Intervention, Comparator, Outcome) format. MEDLINE (via PubMed) and the Cochrane Library were systematically searched for relevant literature, which was supplemented by manual searches. References were screened for inclusion, and vetted evaluation tools were used to assess the quality of included studies, to extract data, and to grade the level of evidence supporting each recommendation or statement. The quality of the evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Graded recommendations and ungraded consensus-based statements were drafted and voted on using a modified Delphi technique to achieve consensus. A diagnostic algorithm is provided, using supporting data from the recommendations where possible, along with expert consensus to help physicians gauge the probability of HP. RESULTS: The systematic review of the literature based on 14 PICO questions resulted in 14 key action statements: 12 evidence-based, graded recommendations and 2 ungraded consensus-based statements. All evidence was of very low quality. INTERPRETATION: Diagnosis of HP should employ a patient-centered approach and include a multidisciplinary assessment that incorporates the environmental and occupational exposure history and CT pattern to establish diagnostic confidence prior to considering BAL and/or lung biopsy. Criteria are presented to facilitate diagnosis of HP. Additional research is needed on the performance characteristics and generalizability of exposure assessment tools and traditional and new diagnostic tests in modifying clinical decision-making for HP, particularly among those with a provisional diagnosis.

4.
Chest ; 159(3): e151-e154, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33678283

RESUMO

CASE PRESENTATION: A 64-year-old previously healthy man presented with 8 weeks of progressive dyspnea on exertion and cough. Prior to presentation, the patient was able to bicycle > 60 miles per week and work full-time in a home improvement store. He was up-to-date with age-appropriate cancer screening and immunizations, and home medications included famotidine for reflux and nonsteroidal antiinflammatories for osteoarthritis, both as-needed. He had no significant respiratory exposure, aside from previous work as an electrician. His symptoms began in mid-February 2020 amid the coronavirus disease 2019 pandemic, although he had no known exposure to the virus.


Assuntos
/diagnóstico , Frutose-Bifosfato Aldolase/sangue , Glucocorticoides/administração & dosagem , Pulmão/diagnóstico por imagem , Miosite , Troca Plasmática/métodos , Rituximab/administração & dosagem , Treonina-tRNA Ligase/imunologia , Autoanticorpos/sangue , Diagnóstico Diferencial , Progressão da Doença , Humanos , Imunossupressores/administração & dosagem , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/diagnóstico , Debilidade Muscular/etiologia , Miosite/sangue , Miosite/diagnóstico , Miosite/fisiopatologia , Miosite/terapia , Oxigenoterapia/métodos , Prognóstico , Resultado do Tratamento
6.
Eur Respir J ; 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008934

RESUMO

This phase 2, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of lebrikizumab, an interleukin-13 monoclonal antibody, alone or with background pirfenidone therapy, in patients with idiopathic pulmonary fibrosis (IPF).Patients with IPF aged ≥40 years with % predicted forced vital capacity (%FVC) 40%-100% and diffusing capacity for carbon monoxide 25%-90% and who were treatment-naive (Cohort A) or receiving pirfenidone (2403 mg·day-1; Cohort B) were randomised 1:1 to receive lebrikizumab 250 mg or placebo subcutaneously every 4 weeks. The primary endpoint was annualised rate of %FVC decline over 52 weeks.In Cohort A, 154 patients were randomised to receive lebrikizumab (n=78) or placebo (n=76). In Cohort B, 351 patients receiving pirfenidone were randomised to receive lebrikizumab (n=174) or placebo (n=177). Baseline demographics were balanced across treatment arms in both cohorts. The primary endpoint (annualised rate of %FVC decline) was not met in Cohort A (lebrikizumab versus placebo, -5.2% versus -6.2%; p=0.456) or Cohort B (lebrikizumab versus placebo, -5.5% versus -6.0%; p=0.557). In Cohort B, a non-statistically significant imbalance in mortality favouring combination therapy was observed (hazard ratio, 0.42 [95% CI, 0.17-1.04]). Pharmacodynamic biomarkers indicated lebrikizumab activity. The safety profile was consistent with that in previous studies of lebrikizumab and pirfenidone as monotherapies.Lebrikizumab alone or with pirfenidone was not associated with reduced %FVC decline over 52 weeks despite evidence of pharmacodynamic activity. Lebrikizumab was well tolerated with a favourable safety profile. These findings suggest that blocking IL-13 may not be sufficient to achieve a lung function benefit in patients with IPF.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32721166

RESUMO

Rationale Usual interstitial pneumonia (UIP) is the defining morphology of idiopathic pulmonary fibrosis (IPF). Guidelines for IPF diagnosis conditionally recommend surgical lung biopsy (SLB) for histopathology diagnosis of UIP when radiology and clinical context are not definitive. A 'molecular diagnosis of UIP' in transbronchial lung biopsy (TBBx), the Envisia Genomic Classifier, accurately predicted histopathologic UIP. Objectives We evaluated the combined accuracy of the Envisia Genomic Classifier and local radiology in the detection of UIP pattern. Methods Ninety-six patients who had diagnostic lung pathology, as well as a TBBx for molecular testing with Envisia Genomic Classier, were included in this analysis. The classifier results were scored against reference pathology. UIP identified on HRCT as documented by features in local radiologists' reports was compared to histopathology. Measurements and Main Results In 96 patients, the Envisia classifier achieved a specificity of 92.1% [CI:78.6%-98.3%] and a sensitivity of 60.3% [CI:46.6%-73.0%] for histology-proven UIP pattern. Local radiologists identified UIP in 18 of 53 patients with UIP histopathology with a sensitivity of 34.0% [CI:21.5%-48.3%], and a specificity of 96.9% [CI:83.8 - 100]). In conjunction with HRCT patterns of UIP, the Envisia classifier results identified 24 additional UIP patients (sensitivity 79.2% specificity 90.6%). Conclusions In 96 patients with suspected ILD, the Envisia Genomic Classifier identified UIP regardless of HRCT pattern. These results suggest that recognition of a UIP pattern by the Envisia Genomic Classifier combined with HRCT and clinical factors in a multidisciplinary discussion may assist clinicians in making an ILD (especially IPF) diagnosis without the need for SLB.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32634038

RESUMO

RATIONALE: Several new drugs for idiopathic pulmonary fibrosis (IPF) are in development. Tools are needed to assess whether these drugs benefit patients on outcomes that matter most to them. Health-related quality of life (HRQL) is one such outcome. It is influenced by many factors, but symptoms and their impacts are two strong drivers. OBJECTIVES: To develop a questionnaire to assess symptoms, disease impacts and HRQL specifically for patients with IPF. METHODS: Working with the U.S. Food and Drug Administration through the Drug Development Tool Qualification process, focus groups, concept elicitation and cognitive debriefing interviews were conducted to inform the development of a 44-item pilot questionnaire. The pilot paper-and-pen questionnaire was migrated to an equivalent electronic version and field tested in a 14-day study. Response data were subjected to psychometric testing, including exploratory factor analysis, item calibration using item response theory models, test-retest reliability, and validity testing. MEASUREMENTS AND MAIN RESULTS: 125 patients with IPF (62.4% men) completed the longitudinal study. The mean (±SD) age of the cohort was 69±7.60 years, and the mean percent predicted forced vital capacity (FVC%) was 71%±20.0. After factor and item analyses, 35 items were retained, and these comprise the two modules (Symptoms and Impacts) of the Living with IPF (L-IPF) questionnaire. The L-IPF yields five scales demonstrating good psychometric properties, including correlation with concurrently-collected FVC% and the ability to discriminate between patients with differing levels of IPF severity. CONCLUSIONS: The L-IPF is a new questionnaire that assesses symptoms, disease impacts and HRQL in patients with IPF. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

9.
BMC Pulm Med ; 20(1): 191, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32664913

RESUMO

BACKGROUND: In patients with idiopathic pulmonary fibrosis (IPF) treated with pirfenidone (Esbriet®, Genentech USA, Inc. South San Francisco, CA.), effectively managing treatment-related adverse events (AEs) may improve adherence. Due to a lack of clinical evidence and expertise, managing these AEs can be challenging for patients and physicians alike. In the absence of evidence, consensus recommendations from physicians experienced in using pirfenidone to treat IPF are beneficial. METHODS: Using a modified Delphi process, expert recommendations were developed by a panel of physicians experienced with using pirfenidone for IPF. Over three iterations, panelists developed and refined a series of statements on the use of pirfenidone in IPF. Their agreement on each statement was ranked using a Likert scale. RESULTS: A panel of 12 physicians participated and developed a total of 286 statements on dosing and administration, special populations, drug-drug interactions, laboratory analysis, warnings and precautions, and AE management. Expert recommendations were achieved with regard to slower initial titrations and slower titrations for AEs, dosing with meal(s) or substantial meals, and adding other prescribed pharmacological agents for AEs. CONCLUSION: Until there is further clinical evidence, the resulting consensus recommendations are intended to provide direction on the practical management of IPF with pirfenidone, by encompassing a broad experience from the real world to complement data gleaned from clinical trials.

10.
J Scleroderma Relat Disord ; 5(2 Suppl): 48-60, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32455167

RESUMO

Systemic sclerosis (SSc) is a progressive vasculopathic, fibrosing autoimmune condition, portending significant mortality; wherein interstitial lung disease (ILD) is the leading cause of death. Although lacking a definitive cure, therapeutics for (SSc-ILD) that stave progression exist with further promising primary and adjuvant compounds in development, as well as interventions to reduce symptom burden and increase quality of life. To date, there has been a significant but varied history related to systemic sclerosis-related interstitial lung disease trial design and endpoint designation. This is especially true of endpoints measuring patient-reported perceptions of efficacy and tolerability. This article describes the underpinnings and complexity of the science, methodology, and current state of patient-reported outcome measures used in (SSc-ILD) systemic sclerosis-related interstitial lung disease in clinical practice and trials.

11.
Eur Respir J ; 55(5)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139456

RESUMO

INTRODUCTION: Sarcoidosis-associated pulmonary hypertension (SAPH) is associated with reduced survival in single-centre studies. The 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 enrolment. Information analysed includes right heart catheterisation data, pulmonary function testing, chest radiography, Scadding stage and 6-min walk distance (6MWD), among others. Cox regression models were used to identify independent predictors of transplant-free survival. RESULTS: Data from 215 patients followed for a mean±sd 2.5±1.9 years were available for analysis. In the 159 precapillary patients, the Kaplan-Meier-adjusted 1-, 3- and 5-year transplant-free survival was 89.2%, 71.7% and 62.0%, respectively. Kaplan-Meier-adjusted 1-, 3- and 5-year transplant-free survival in the incident group was 83.5%, 70.3% and 58.3%, respectively, and in the prevalent group was 94.7%, 72.2% and 66.3%, respectively. Patients with reduced diffusing capacity of the lung for carbon monoxide (D LCO) (<35% predicted) and 6MWD <300 m in the precapillary cohort had significantly worse transplant-free survival. Reduced 6MWD and preserved forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio were identified as independent risk factors for reduced transplant-free survival in the precapillary cohort. CONCLUSION: Reduced D LCO (<35% pred) and 6MWD (<300 m) at the time of registry enrolment were associated with reduced transplant-free survival in the overall precapillary cohort. Preserved FEV1/FVC ratio was identified as an independent risk factor for worsened outcomes.

12.
Eur Respir Rev ; 29(155)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32198217

RESUMO

A variety of phenotypic categorisations have been developed for sarcoidosis. Phenotyping has been used for genetics studies and to guide treatment selection. The authors participated in a Delphi expert consensus panel to develop a proposed phenotype categorisation and treatment recommendations for pulmonary sarcoidosis patients. Panellists reached consensus that asymptomatic patients with normal pulmonary function and adenopathy alone or normal chest imaging do not require therapy, while symptomatic patients with impaired pulmonary function or infiltrates should be treated. The panel did not reach consensus on asymptomatic patients with abnormal chest imaging or reduced pulmonary function, or symptomatic patients with normal chest imaging and pulmonary function. The proposed phenotype categories and associated treatment recommendations are asymptomatic (no therapy), acute (disease duration <1-2 years, apparently self-limited, corticosteroids), chronic (antimetabolites and other second-line therapies) and advanced (biologics). Some clinical settings, such as dyspnoea/hypoxaemia at rest, severely impaired or rapidly decreasing pulmonary function tests, and severe cardiac, neurologic, ocular or renal involvement warrant immediate therapy.

13.
Eur Respir Rev ; 29(155)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32198218

RESUMO

Pulmonary sarcoidosis presents substantial management challenges, with limited evidence on effective therapies and phenotypes. In the absence of definitive evidence, expert consensus can supply clinically useful guidance in medicine. An international panel of 26 experts participated in a Delphi process to identify consensus on pharmacological management in sarcoidosis with the development of preliminary recommendations.The modified Delphi process used three rounds. The first round focused on qualitative data collection with open-ended questions to ensure comprehensive inclusion of expert concepts. Rounds 2 and 3 applied quantitative assessments using an 11-point Likert scale to identify consensus.Key consensus points included glucocorticoids as initial therapy for most patients, with non-biologics (immunomodulators), usually methotrexate, considered in severe or extrapulmonary disease requiring prolonged treatment, or as a steroid-sparing intervention in cases with high risk of steroid toxicity. Biologic therapies might be considered as additive therapy if non-biologics are insufficiently effective or are not tolerated with initial biologic therapy, usually with a tumour necrosis factor-α inhibitor, typically infliximab.The Delphi methodology provided a platform to gain potentially valuable insight and interim guidance while awaiting evidenced-based contributions.

14.
Eur Respir Rev ; 29(155)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32198219

RESUMO

In patients treated with repository corticotrophin injection (RCI) for pulmonary sarcoidosis, effective management of adverse events may improve adherence. However, management of adverse events may be challenging due to limitations in real-world clinical experience with RCI and available published guidelines.We surveyed 12 physicians with a modified Delphi process using three questionnaires. Questionnaire 1 consisted of open-ended questions. Panellists' answers were developed into a series of statements for Questionnaires 2 and 3. In these, physicians rated their agreement with the statements using a Likert scale.Key consensus recommendations included a starting dose of 40 units twice a week for patients with less severe disease, continued at a maintenance dose for patients who responded, particularly those with chronic refractory sarcoidosis. Panellists reached consensus that concomitant steroids should be quickly tapered in patients receiving RCI, but that concomitant use of immunosuppressive medications should be continued. Panellists developed consensus recommendations for adverse event management, and reached consensus that RCI should be down-titrated or discontinued if other interventions for the adverse effects fail or if the adverse effect is severe.In the absence of clinical evidence, our Delphi consensus opinions may provide practical guidance to physicians on the management of RCI to treat pulmonary sarcoidosis.

15.
Lancet Respir Med ; 8(1): 25-33, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575509

RESUMO

BACKGROUND: Connective tissue growth factor (CTGF) is a secreted glycoprotein that has a central role in the process of fibrosis. This study was designed to assess the safety, tolerability, and efficacy of pamrevlumab (FG-3019), a fully recombinant human monoclonal antibody against CTGF, in idiopathic pulmonary fibrosis. The aim was to establish whether pamrevlumab could slow, stop, or reverse progression of idiopathic pulmonary fibrosis. METHODS: The phase 2, randomised, double-blind, placebo-controlled PRAISE trial was done at 39 medical centres in seven countries (Australia, Bulgaria, Canada, India, New Zealand, South Africa, and the USA). Patients with idiopathic pulmonary fibrosis and percentage of predicted forced vital capacity (FVC) of 55% or greater were enrolled and randomly assigned (1:1) by use of interactive responsive technology to intravenous infusion of pamrevlumab 30 mg/kg or placebo every 3 weeks over 48 weeks (16 infusions). The primary efficacy outcome was change from baseline in percentage of predicted FVC at week 48. Disease progression (defined as a decline from baseline in percentage of predicted FVC of ≥10%, or death) at week 48 was a key secondary efficacy outcome. All patients in the pamrevlumab group received at least one dose of the study drug and were analysed for safety. Two patients in the placebo group were excluded from the intention-to-treat population for the efficacy analyses because of enrolment error. This trial is registered with ClinicalTrials.gov, NCT01890265. FINDINGS: Between Aug 17, 2013, and July 21, 2017, 103 patients were randomly assigned (50 to pamrevlumab and 53 to placebo). Pamrevlumab reduced the decline in percentage of predicted FVC by 60·3% at week 48 (mean change from baseline -2·9% with pamrevlumab vs -7·2% with placebo; between-group difference 4·3% [95% CI 0·4-8·3]; p=0·033). The proportion of patients with disease progression was lower in the pamrevlumab group than in the placebo group at week 48 (10·0% vs 31·4%; p=0·013). Pamrevlumab was well tolerated, with a safety profile similar to that of placebo. Treatment-emergent serious adverse events were observed in 12 (24%) patients in the pamrevlumab group and eight (15%) in the placebo group, with three patients on pamrevlumab and seven on placebo discontinuing treatment. Of the three (6%) deaths in the pamrevlumab group and six (11%) in the placebo group, none was considered treatment related. INTERPRETATION: Pamrevlumab attenuated progression of idiopathic pulmonary fibrosis and was well tolerated. Now in phase 3 development, pamrevlumab shows promise as a novel, safe, and effective treatment for idiopathic pulmonary fibrosis. FUNDING: FibroGen.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Fator de Crescimento do Tecido Conjuntivo/administração & dosagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Fator de Crescimento do Tecido Conjuntivo/efeitos adversos , Fator de Crescimento do Tecido Conjuntivo/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Capacidade Vital/efeitos dos fármacos
17.
Respir Med ; 150: 120-125, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30961937

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by irreversible loss of lung function and an unpredictable course of disease progression. METHODS: The safety data for patients with IPF who received placebo in 6 clinical trials were pooled to examine the categories and frequencies of serious adverse events (SAEs) in this population. RESULTS: In 1082 patients with IPF who received placebo, 673 SAEs were reported. Of these, 93 SAEs resulted in death (8.6% of patients). Respiratory-related conditions were the most frequently reported SAE (225 events, 16.33 per 100 patient-exposure years [PEY]), followed by infections and infestations (136 events, 9.87 per 100 PEY) and cardiac disorders (79 events, 5.73 per 100 PEY); these categories also had the most fatal outcomes (60, 10, and 10 deaths, respectively). The most frequently reported fatal respiratory-related SAEs were IPF and respiratory failure (38 and 11 patients, respectively), and the most frequently reported fatal infections and infestations and cardiac disorders were pneumonia (5 patients) and myocardial infarction (3 patients), respectively. CONCLUSIONS: This pooled analysis has value as a comparator for safety in future studies of IPF and provides insights in the natural evolution of both IPF and common comorbidities.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/mortalidade , Placebos/efeitos adversos , Segurança/estatística & dados numéricos , Idoso , Comorbidade , Progressão da Doença , Feminino , Cardiopatias/epidemiologia , Humanos , Fibrose Pulmonar Idiopática/epidemiologia , Fibrose Pulmonar Idiopática/fisiopatologia , Infecções/epidemiologia , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Placebos/administração & dosagem , Pneumonia/epidemiologia , Testes de Função Respiratória/métodos , Insuficiência Respiratória/epidemiologia
18.
J Mol Med (Berl) ; 96(12): 1375-1385, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30353303

RESUMO

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, and long-term oxygen therapy has been shown to reduce mortality in COPD patients with severe hypoxemia. However, the Long-term Oxygen Treatment Trial (LOTT), a large randomized trial, found no benefit of oxygen therapy in COPD patients with moderate hypoxemia. We hypothesized that there may be differences in response to oxygen which depend on genotype or gene expression. In a genome-wide time-to-event analysis of the primary outcome of death or hospitalization in 331 subjects, 97 single nucleotide polymorphisms (SNPs) showed evidence of interaction with oxygen therapy at P < 1e-5, including 7 SNPs near arylsulfatase B (ARSB; P = 6e-6). In microarray expression profiling on 51 whole blood samples from 37 individuals, at screening and/or at 12-month follow-up, ARSB expression was associated with the primary outcome depending on oxygen treatment. The significant SNPs were conditional expression quantitative trait loci for ARSB expression. In a network analysis of genes affected by long-term oxygen, two observed clusters including 26 co-expressed genes were enriched in mitochondrial function. Using data from the observational COPDGene Study, we validated the expression of 25 of these 26 genes, plus ARSB. The effect of long-term oxygen therapy in COPD varied based on ARSB expression and genotype. ARSB has previously been shown to be associated with hypoxemia in human bronchial and colonic epithelial cells and in a mouse model. In peripheral blood, long-term oxygen treatment affected expression of mitochondrial-related genes, a biologically relevant pathway in COPD. SNPs and expression of ARSB are associated with response to long-term oxygen in COPD. The ARSB SNPs were expression quantitative trait loci depending on oxygen therapy. Genes differentially expressed by long-term oxygen were enriched in mitochondrial functions. This suggests a potential biomarker to personalize use of long-term oxygen in COPD.


Assuntos
Oxigênio/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/terapia , Idoso , Idoso de 80 Anos ou mais , Feminino , Expressão Gênica , Genômica , Humanos , Masculino , Pessoa de Meia-Idade
19.
Lancet Respir Med ; 6(9): 707-714, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30100404

RESUMO

BACKGROUND: Abnormal acid gastro-oesophageal reflux (GER) is hypothesised to play a role in progression of idiopathic pulmonary fibrosis (IPF). We aimed to determine whether treatment of abnormal acid GER with laparoscopic anti-reflux surgery reduces the rate of disease progression. METHODS: The WRAP-IPF trial was a randomised controlled trial of laparoscopic anti-reflux surgery in patients with IPF and abnormal acid GER recruited from six academic centres in the USA. We enrolled patients with IPF, abnormal acid GER (DeMeester score of ≥14·7; measured by 24-h pH monitoring) and preserved forced vital capacity (FVC). We excluded patients with a FVC below 50% predicted, a FEV1/FVC ratio of less than 0·65, a history of acute respiratory illness in the past 12 weeks, a body-mass index greater than 35, and known severe pulmonary hypertension. Concomitant therapy with nintedanib and pirfenidone was allowed. The primary endpoint was change in FVC from randomisation to week 48, in the intention-to-treat population with mixed-effects models for repeated measures. This trial is registered with ClinicalTrials.gov, number NCT01982968. FINDINGS: Between June 1, 2014, and Sept 30, 2016, we screened 72 patients and randomly assigned 58 patients to receive surgery (n=29) or no surgery (n=29). 27 patients in the surgery group and 20 patients in the no surgery group had an FVC measurement at 48 weeks (p=0·041). Intention-to-treat analysis adjusted for baseline anti-fibrotic use demonstrated the adjusted rate of change in FVC over 48 weeks was -0·05 L (95% CI -0·15 to 0·05) in the surgery group and -0·13 L (-0·23 to -0·02) in the non-surgery group (p=0·28). Acute exacerbation, respiratory-related hospitalisation, and death was less common in the surgery group without statistical significance. Dysphagia (eight [29%] of 28) and abdominal distention (four [14%] of 28) were the most common adverse events after surgery. There was one death in the surgery group and four deaths in the non-surgery group. INTERPRETATION: Laparoscopic anti-reflux surgery in patients with IPF and abnormal acid GER is safe and well tolerated. A larger, well powered, randomised controlled study of anti-reflux surgery is needed in this population. FUNDING: US National Institutes of Health National Heart, Lung and Blood Institute.


Assuntos
Refluxo Gastroesofágico/cirurgia , Fibrose Pulmonar Idiopática/cirurgia , Laparoscopia , Idoso , Progressão da Doença , Feminino , Refluxo Gastroesofágico/complicações , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/mortalidade , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Capacidade Vital
20.
Respir Med ; 139: 72-78, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29858005

RESUMO

BACKGROUND: Pulmonary hypertension (PH) is a significant cause of morbidity and mortality in sarcoidosis. We established a multi-national registry of sarcoidosis associated PH (SAPH) patients. METHODS: Sarcoidosis patients with PH confirmed by right heart catheterization (RHC) were studied. Patients with pulmonary artery wedge pressure (PAWP) of 15 mmHg or less and a mean pulmonary artery pressure (mPAP) ≥ 25 Hg were subsequently analyzed. Data collected included hemodynamics, forced vital capacity (FVC), diffusion capacity of carbon monoxide (DLCO), chest x-ray, and 6-min walk distance (6MWD). RESULTS: A total of 176 patients were analyzed. This included 84 (48%) cases identified within a year of entry into the registry and 94 (53%) with moderate to severe PH. There was a significant correlation between DLCO percent predicted (% pred) andmPAP (Rho = -0.228, p = 0.0068) and pulmonary vascular resistance (PVR) (Rho = -0.362, p < 0.0001). PVR was significantly higher in stage 4 disease than in stage 0 or 1 disease (p < 0.05 for both comparisons). About two-thirds of the SAPH patients came from the United States (US). There was a significant difference in the rate of treatment between US (67.5%) versus non-US (86%) (Chi Square 11.26, p = 0.0008) sites. CONCLUSIONS: The clinical features of SAPH were similar across multiple centers in the US, Europe, and the Middle East. The severity of SAPH was related to reduced DLCO. There were treatment differences between the US and non-US centers.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Sarcoidose Pulmonar/complicações , Sarcoidose Pulmonar/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cateterismo Cardíaco , Europa (Continente) , Feminino , Hemodinâmica , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Oriente Médio , Sistema de Registros , Sarcoidose Pulmonar/diagnóstico por imagem , Sarcoidose Pulmonar/etiologia , Estados Unidos , Capacidade Vital , Teste de Caminhada , Raios X
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