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Background: Interstitial lung disease (ILD) is the main clinical feature of antisynthetase syndrome (ASS). In the absence of randomized controlled trials to guide therapy, treatment strategies are often extrapolated from other diseases, mainly systemic sclerosis (SSc). Objectives: Our aim was to evaluate the dynamics of ILD severity following immunosuppressive treatment (IST) in ASS compared to SSc. Design: A multicenter retrospective observational study. Methods: ASS (n = 22) and SSc (n = 32) subjects with ILD were included in the registries of three medical centers. All patients received ISTs. We analyzed changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide corrected for hemoglobin (DLCOc) after treatment initiation using linear mixed-effects models. Changes in high-resolution chest CT scans were analyzed by a radiologist blinded to clinical data. Results: The median (interquartile range) age was 66 (59–71), 72% were females, and 81% of IST included mycophenolate mofetil (MMF). Baseline demographics, comorbidities, and pulmonary functions were similar between the groups. Among the ASS group, the mixed-effects models showed significant improvements in FVC% (F = 11.3, p < 0.01) and DLCOc% (F = 7.1, p = 0.015) after treatment initiation over time, while in the SSc group, there were no significant changes in FVC% (F = 0.4, p = 0.551) and DLCOc% (F = 0.8, p = 0.384). Changes in FVC% and DLCOc% were higher in the ASS group compared with SSc (p = 0.017 and p < 0.01, respectively), which persisted after adjustment to steroid use and in a sub-analysis of patients with serial pre- and post-IST pulmonary functions. Both groups had improved total CT scores after IST, without changes in other radiologic scores. Conclusion: Immunosuppressive treatment, mostly with MMF, was associated with significant improvement of FVC% and DLCOc% in ASS, compared to their stabilization only in SSc. This should encourage future randomized controlled studies of MMF in ASS patients. Plain language summary How interstitial lung disease progresses after immunosuppressive treatment in antisynthetase syndrome vs. systemic sclerosis Antisynthetase syndrome (ASS) is a rare autoimmune disease that affects the muscles, joints and lungs. Systemic sclerosis (SSc) is also a less rare autoimmune disease that causes scarring of the skin and the lungs, for which there is more abundant clinical trial evidence to support treatment. For both diseases, immunosuppressive treatments are required, which are treatments that lower the activity of the body’s immune system. As there are no official treatment guidelines for managing ASS lung disease, doctors often rely on established treatments for SSc lung disease. For this reason, our aim was to assess how lung disease responds to immunosuppressive treatment in ASS compared to SSc. We looked back at data of 54 patients from three medical center. 22 patients had ASS lung disease and 32 patients had SSc lung disease, all treated with immunosuppressive therapy. We found that lung function has significantly improved in the ASS group after treatment. This improvement was greater than that observed in the SSc group. CT scans, which depict the changes in the relevant lung disease, showed improvements in both groups. Additionally, we identified markers that may help predict how patients with ASS will respond to immunosuppressive treatments. In summary, we found major improvements of ASS lung disease compared to SSc after starting immunosuppressive therapy, supporting the need for additional high-quality research that focus on ASS.

Background: There have been no previous comprehensive reports on interstitial lung diseases (ILD) in Israeli population, that may have unique epidemiological features. We aimed to explore ILD in Israel, with an emphasis on disparities between different regions of the country. Methods: The study included consecutive patients with a multidisciplinary diagnosis of ILD, using data from registries of four tertiary medical centers (MC) located in Central and Northern Israel. Multivariate regression models were used to assess the region of residence (peripheral vs. central) as an independent predictor for ILD subtypes. Results: Included were 927 patients with ILD (mean age 67 ± 13, 40% females). Most patients (56–61%) reported working in at least one job that involved relevant inhalational exposures. Despite the geographic proximity of MCs (all within 100 km), significant variations in demographic and clinical characteristics were observed, including age, sex, exposures, and ILD diagnoses (p < 0.01). The most prevalent diagnoses were Idiopathic pulmonary fibrosis (IPF, range 13–58%) and autoimmune-related ILD (11–30%). In peripheral areas, the diagnosis of IPF was more frequent (53% vs. 24%, p < 0.01), while exposure-related ILD (5% vs. 16%, p < 0.01) and autoimmune-related ILD (16% vs. 25%, p < 0.01) were more frequent in central Israel. In multivariate analysis, peripheral residence remained an independent predictor for IPF (AOR 2.95, 95% CI 2.1–4.1) and central residence for exposure-related ILD (AOR 0.46, 95% CI 0.33–0.63). Conclusions: Variations in ILD characteristics were observed between centers in close geographic proximity, highlighting disparities between peripheral and central Israel, and the need for personalized assessment based on local frequencies and exposures.

Introduction Lung cancer remains the leading cause of death from cancer, worldwide. Developing early detection diagnostic methods, especially non-invasive methods, is a critical component to raising the overall survival rate and prognosis for lung cancer. The purpose of this study is to evaluate two protocols of a novel in vitro cellular immune response test to detect lung cancer. The test specifically quantifies the glycolysis metabolism pathway, which is a biomarker for the activation level of immune cells. It summarizes the results of two clinical trials, where each deploys a different protocol's version of this test for the detection of lung cancer. In the later clinical trial, an improved test protocol is applied. Method The test platform is based on changes in the metabolic pathways of the immune cells following their activation by antigenic stimuli associated with Lung cancer. Peripheral Blood Mononuclear Cells are loaded on a multiwell plate together with various lung tumor associated antigens and a fluorescent probe that exhibits a pH-dependent absorption shift. The acidification process in the extracellular fluid is monitored by a commercial fluorescence plate reader device in continuous reading for 3 h at 37 °C to document the fluorescent signal received from each well. Results In the later clinical trial, an improved test protocol was applied and resulted in increased test accuracy. Specificity of the test increased to 94.0% and test sensitivity increased to 97.3% in lung cancer stage I, by using the improved protocol. Conclusion The improved protocol of the novel cellular immune metabolic response based test detects stage I and stage II of lung cancer with high specificity and sensitivity, with low material costs and fast results.

The current understanding of pulmonary hypertension (PH) due to left ventricular diseases does not distinguish heart failure (HF) with reduced ejection fraction (HFrEF) from HF and preserved ejection fraction (HFpEF), in terms of pulmonary hemodynamics. The value of pulmonary vascular compliance (PCa) and diastolic pulmonary gradient (DPG) as predictors of survival in either HF syndrome is controversial. The aims of our study were to compare the pulmonary hemodynamics in the two HF phenotypes, given similar values of pulmonary artery wedge pressure (PAWP), and to evaluate the impact of PCa and DPG on survival. We retrospectively reviewed the charts of 168 PH-HFrEF and 86 PH-HFpEF patients. The independent association of PCa and DPG with prognosis was assessed by means of a Cox proportional hazard model. All cause survival was analyzed over an average follow-up period of 50 months. PH-HFpEF patients had a significantly higher DPG than PH-HFrEF patients (6.1±7.1 vs 1.8±4.5 mmHg, adjusted P=.025). PCa was similar in PH-HFpEF and PH-HFrEF. PCa was a significant predictor of survival, according to previously described preset cutoffs (2.15 mL/mmHg in HFrEF and 1.1 mL/mmHg in HFpEF) and based on a continuous scale; whereas DPG had no impact on survival in both patients groups. Our findings suggest that for similar levels of PAWP, pulmonary circulation may be stiffer in patients with HFpEF-PH than patients with HFrEF-PH, leading to higher DPGs. Nonetheless, PCa rather than DPG emerged as the stronger predictor of survival in both left-sided PH phenotypes.

Introduction Non-tuberculous mycobacteria pulmonary disease (NTM-pd) commonly complicates bronchiectasis. However, clinical and radiological features of NTM-pd and bronchiectasis are very similar. We aimed to develop a radiologic prediction tool for bronchiectasis to identify NTM-pd. Methods We reviewed clinical, laboratory and radiological data in patients with bronchiectasis. Radiologic features on CT scans and the individual components of the Bhalla scoring system were compared between people with and without NTM-pd. Logistic regression and receiver-operating curve (ROC) analysis were performed to predict NTM-pd. Results People with NTM-pd had more pulmonary segments with bronchiectasis (13 ± 5 vs. 11 ± 5, p  = 0.03), presence of mucus plugging (47% vs. 19%, p  < 0.0001) and tree in bud infiltrates (53% vs. 28%, p  = 0.004). The total modified- Bhalla score was worse among people with NTM-pd (median [IQR] 11[9,13] vs. 9[8,12], p  = 0.03). Logistic regression identified the number of pulmonary segments involved, presence of bullae, consolidations, and a total score of 10 or more to be independently associated with presence of NTM-pd. ROC analysis with radiographic variables only identified an AUC of 0.706 (95% CI 0.644–0.762). When people with chronic Pseudomonas infection were excluded from the ROC analysis, prediction for NTM was improved: AUC = 0.87 (95% CI 0.796–0.945). Discussion and Conclusions Radiological features together with advanced age and female gender may predict NTM-pd among people with bronchiectasis. Infection with Pseudomonas aeruginosa may resemble NTM radiographically, and this prediction rule may better differentiate people with and without NTM-pd when Pseudomonas infection is not present.

Background The burden of symptoms and risk of exacerbations are the main drivers of the overall assessment of the Chronic Obstructive Pulmonary Disease (COPD) and the adequate treatment approaches per current Global Initiative for Chronic Obstructive Lung Disease (GOLD). Physical activity has emerged as both functional outcome and non-pharmacological intervention in COPD patients, despite the lack of standardized measures or guidelines in clinical practice. This study aimed to explore in more depth the 24-h respiratory symptoms, the physical activity level (PAL) and the relationship between these two determinants in stable COPD patients. Methods This was a multinational, multicenter, observational, cross-sectional study conducted in ten European countries and Israel. Dedicated questionnaires for each part of the day (morning, daytime, night) were used to assess respiratory symptoms. PAL was evaluated with self- and interview-reported tools [EVS (exercise as vital sign) and YPAS (Yale Physical Activity Survey)], and physician’s judgement. Patients were stratified in ABCD groups by 2013 and 2017 GOLD editions using the questionnaires currently recommended: modified Medical Research Council dyspnea scale and COPD Assessment Test. Results The study enrolled 2190 patients (mean age: 66.9 years; male: 70.0%; mean % predicted FEV1: 52.6; GOLD groups II-III: 84.5%; any COPD treatment: 98.9%). Most patients (> 90%) reported symptoms in any part of the 24-h day, irrespective of COPD severity. PAL evaluations showed discordant results between patients and physicians: 32.9% of patients considered themselves completely inactive, while physicians judged 11.9% patients as inactive. By YPAS, the overall study population spent an average of 21.0 h/week performing physical activity, and 68.4% of patients were identified as sedentary. In any GOLD ABCD group, the percentage of inactive patients was high. Our study found negative, weak correlations between respiratory symptoms and self-reported PAL ( p  < 0.001). Conclusions Despite regular treatment, the majority of stable COPD patients with moderate to severe disease experienced daily variable symptoms. Physical activity level was low in this COPD cohort, and yet overestimated by physicians. With evidence indicating the negative consequences of inactivity, its adequate screening, a more active promotion and regular assessment of physical activity are urgently needed in COPD patients for better outcomes. Trial registration NCT03031769 , retrospectively registered, 23 Jan 2017.

Ultrafine particles (UFP) are toxic due to their small size and penetration into deeper lung compartments. We aimed to evaluate the exhaled breath condensate (EBC)-UFP content as a reflection of inflammation and oxidative stress status in COPD patients and as an exacerbation risk marker. EBC was collected by conventional methods. Particles were analyzed with NanoSight LM20. EBC carbonyl and 8-hydroxydeoxyguanosine (8-OHdG) levels were measured using ELISA kits. Study population (58 COPD patients and 40 healthy smoker and non-smoker controls) underwent spirometry, diffusion capacity, EBC testing, and blood sampling. Absolute eosinophil count, C-reactive protein (CRP), and lactate dehydrogenase in serum were elevated in the COPD group compared with the controls (224 U/L, 5 mg/L, and 391 U/L vs 154 U/L, 3 mg/L, and 330 U/L, =0.009, =0.05, and =0.004, respectively). COPD patients had lower UFP concentrations in EBC compared with controls (0.24 E8/mL vs 0.51 E8/mL, ≤0.001). A mirror image was detected in serum: COPD patients had higher UFP concentrations compared with controls (9.8 E8/mL vs 6.7 E8/mL, respectively, =0.03). EBC carbonyl and 8-OHdG levels were higher among COPD patients compared with controls (5.1 per 1 µg/mL protein and 0.036 ng/mL vs 0.41 per 1 µg/mL protein and 0.003 ng/mL, =0.001 and ≤0.001, respectively). EBC UFP concentrations were negatively correlated with pack years ( =-0.44, ≤0.001) and positively correlated with FEV and diffusing lung capacity for carbon monoxide ( =0.46, 0.23, ≤0.001 and =0.04, respectively). Low EBC UFP concentrations (≤0.18 E8/mL) and CRP levels ≥5 mg/L were independent predictors of the frequent exacerbator phenotype (OR 3.6; 95% CI: 1.06-7.97; =0.04 and OR 4.4; 95% CI: 1.24-10.2; =0.02, respectively). UFP content in EBC reflects the inflammatory state of airways. Low UFP concentrations in EBC and high in serum of COPD patients support our hypothesis that increased epithelial permeability could be the mechanism behind those findings.

Hypersensitivity pneumonitis (HP) is a heterogeneous interstitial lung disease (ILD) that may be difficult to confidently diagnose. Recently, the 2020 ATS/JRS/ALAT HP diagnostic guidelines were published, yet data validating their performance in real-life settings are scarce. We aimed to assess the diagnostic performance of the HP guidelines compared to the gold-standard multidisciplinary discussion (MDD). For this purpose, we included consecutive ILD patients that underwent diagnostic bronchoscopy between 2017 and 2020 in three large medical centers. Four diagnostic factors (antigen exposure history, chest computed tomography pattern, bronchoalveolar lavage lymphocyte count, and histology results) were used to assign guidelines-based HP diagnostic confidence levels for each patient. A sensitivity analysis was performed, with MDD diagnosis as the reference standard. Overall, 213 ILD patients were included, 45 (21%) with an MDD diagnosis of HP. The guidelines’ moderate (≥70%) confidence threshold produced optimal performance with 73% sensitivity for HP, 89% specificity, and a J-index of 0.62. The area under the receiver operating characteristic curve (AUC) for a correct guidelines-based diagnosis was 0.86. The guidelines had better performance for non-fibrotic than fibrotic HP (AUC 0.92 vs. 0.82). All diagnostic factors, except bronchoalveolar lavage lymphocyte count, were independent predictors for MDD diagnosis of HP in a multivariate analysis. In conclusion, the HP guidelines exhibited a good diagnostic performance compared to MDD diagnosis in real-life setting.

IntroductionTobacco smoking is a significant source of cadmium exposure among smokers. Most of inhaled heavy metals, including cadmium, are attached to ultrafine particles (UFPs) surface. A low inhaled UFP content in exhaled breath condensate reflects a high inflammatory status of airways. Increased respiratory epithelial permeability and translocation to the circulation is the proposed mechanism. UFP recovered from smokers’ airways have high levels of cadmium compared with the airways of non-smokers.MethodsUrine was collected from 22 smokers subjects and 43 non-smokers. Samples were analysed for UFP and cadmium content. UFP were measured in urine samples by means of the NanoSight LM20 system (NanoSight, UK). A Niton XL3 X-ray fluorescence spectrometer analyzer (Thermo Fischer Scientific, Germany) quantified heavy metal contents in the urine samples.ResultsSmokers had elevated UFP and cadmium content in urine compared with non-smokers (4.6 E8/mL and 20.6 ppm vs 3.4 E8/mL and 18.5 ppm, p=0.05 and p=0.05, respectively). Smokers had elevated levels of lead and rubidium compared with non-smokers (8.9 ppm and 27 ppm vs 7.8 ppm and 2 ppm, p=0.05 and p=0.04, respectively)DiscussionWe suggest that the trajectory of cadmium-related UFP in smokers begins by its inhalation into the airways. The UFPs induce inflammation and oxidative stress in the small airways, are subsequently translocated from the interstitium to the circulation and are finally detected and secreted in urine

Acknowledgments This work was supported by the Israel Lung Association. We would like to express our deepest gratitude and appreciation to Professor Elad Schiff and the Internal Medicine B Department at the Bnai Zion Medical Center for support, mentoring, and making this study possible.