Sputum trypsin-like protease activity relates to clinical outcome in cystic fibrosis.
- 作者列表："Rehill J","Moffitt K","Douglas L","Stuart Elborn J","Jones A","Lorraine Martin S
BACKGROUND:In cystic fibrosis (CF) airways excessive levels of serine trypsin-like proteases (TLPs) activate the epithelial sodium channel (ENaC) resulting in airways dehydration and promotion of mucus secretion. Despite this the relationship of TLP activity and clinical outcome has not been studied. METHODS:We analysed supernatant (sol) prepared from CF sputum from adult CF patients in two study cohorts (29 and 33 samples, respectively). Protease activities were determined by measuring the hydrolysis of peptide-based substrates or by ELISA. Lung function was assessed by spirometry (FEV1). Mortality data was retrospectively obtained and time in months until death or transplantation used for subsequent survival analysis. RESULTS:TLP activity inversely correlated with percent predicted FEV1 (r = -0.4, p = 0.03) and was greater in individuals who did not survive beyond 5-years from the time of sample collection. A Kaplan-Meier analysis demonstrated significantly reduced survival (p = 0.04) for individuals with high TLP activity [hazard ratio (HR) of 7.21 per log unit TLP activity (p = 0.03)]. In contrast, neutrophil elastase displayed no significant associations with lung function or patient survival. Similar findings were evident in the second study cohort. CONCLUSIONS:Sputum TLP activity may represent a novel non-invasive biomarker and/or therapeutic target for CF lung disease.
背景: 在囊性纤维化 (CF) 气道中，过量的丝氨酸胰蛋白酶样蛋白酶 (TLPs) 激活上皮钠通道 (ENaC)，导致气道脱水和促进粘液分泌。尽管如此，尚未研究 TLP 活性与临床结局的关系。 方法: 我们分析了两个研究队列 (分别为 29 份和 33 份样本) 中成人 CF 患者 CF 痰制备的上清液 (sol)。通过测定肽基底物的水解或 ELISA 测定蛋白酶活性。肺功能通过肺活量测定法 (FEV1) 评估。回顾性获得死亡率数据，并在 6 个月内获得时间，直至死亡或移植用于随后的生存分析。 结果: TLP 活性与预计 FEV1 百分比呈负相关 (r =-0.4，p = 0.03)，在样本采集后存活时间未超过 5 年的个体中，TLP 活性更大。Kaplan-Meier 分析显示，高 TLP 活性个体的生存率显著降低 (p = 0.04) [每个日志单位 TLP 活性的风险比 (HR) 为 7.21 (p = 0.03)]。相比之下，中性粒细胞弹性蛋白酶与肺功能或患者生存率无显著相关性。在第二个研究队列中也有类似的发现。 结论: 痰 TLP 活性可能代表 CF 肺病的一种新型非侵入性生物标志物和/或治疗靶点。
METHODS:OBJECTIVES:To asses the clinical course in RA-related interstitial lung disease (RA-ILD) patients with and without rituximab (RTX). The influence of other variables was also evaluated. METHODS:A longitudinal multicentre study was conducted in RA diagnosed with ILD from 2007 until 2018 in Madrid. Patients were included in a registry [pNEumology RhEumatology Autoinmune diseases (NEREA)] from the time of ILD diagnosis. The main endpoint was functional respiratory impairment (FI), when there was a decline ≥5% in the predicted forced vital capacity compared with the previous one. Pulmonary function was measured at baseline and in follow-up visits every 6-12 months. The independent variable was therapy with RTX. Covariables included sociodemographic, clinical, radiological and other therapies. Survival techniques were used to estimate the incidence rate (IR) and 95% CI of functional impairment, expressed per 100 patient-semesters. Cox multivariate regression models were run to examine the influence of RTX and other covariates on FI. Results were expressed as the hazard ratio (HR) and CI. RESULTS:A total of 68 patients were included. FI occurred in 42 patients [IR 23.5 (95% CI 19, 29.1)] and 50% of them had FI within 1.75 years of an ILD diagnosis. A multivariate analysis showed that RTX exposure resulted in a lower risk of FI compared with non-exposure [HR 0.51 (95% CI 0.31, 0.85)]. Interstitial pneumonia, glucocorticoids, disease activity and duration also influenced FI. CONCLUSION:RA-ILD patients deteriorate over time, with the median time free of impairment being <2 years. Patients exposed to RTX had a higher probability of remaining free of FI compared with other therapies. Other factors have also been identified. Key words: rheumatoid arthritis, interstitial lung disease, observational study, rituximab and prognosis
METHODS:The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3–2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2–14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.
METHODS::Bacteria of the Burkholderia cepacia complex (Bcc) are ubiquitous multidrug resistant organisms and opportunistic pathogens capable of causing life threatening lung infections among cystic fibrosis (CF) patients. No effective therapies are currently available to eradicate Bcc bacteria from CF patients, as these organisms are inherently resistant to the majority of clinically available antimicrobials. An immunoproteomics approach was used to identify Bcc proteins that stimulate the humoral immune response of the CF host, using bacterial cells grown under conditions mimicking the CF lung environment and serum samples from CF patients with a clinical record of Bcc infection. 24 proteins of the Bcc strain B. cenocepacia J2315 were identified as immunoreactive, 19 here reported as immunogenic for the first time. Ten proteins were predicted as extracytoplasmic, 9 of them being conserved in Bcc genomes. The immunogenic Bcc extracytoplasmic proteins are potential targets for development of novel therapeutic strategies and diagnostic tools to protect patients against the onset of chronic Bcc lung infections.