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BACKGROUND: Lung transplantation (LTx) is an established treatment option for patients with end-stage lung diseases. Nevertheless, exercise intolerance, respiratory muscle function impairment, functional disability, and peripheral muscle weakness often persist following LTx. PURPOSE: To examine the effectiveness of a pulmonary rehabilitation (PR) program and home-based inspiratory muscle training (IMT) alone or in combination, in post lung transplantation (LTx) patients. METHODS: In a prospective pilot study a sample of 22 patients who had undergone LTx 4–18 months prior, were randomized to groups of PR alone, or combined with home-based IMT, or IMT alone, for six months: four months in the intervention program and two months of follow-up. Inspiratory muscle strength was assessed by measuring the maximal inspiratory pressure (MIP). RESULTS: There was a statistically significant increase in MIP values as well as in the 6-min-walk-test, only in the PR combined with home-based IMT, and IMT exercise groups. From baseline after 2- and 4-months intervention and at 6-months at follow-up, there was a statistically significant correlation between MIP and Maximum Voluntary Ventilation (MVV) values. CONCLUSIONS: Pulmonary rehabilitation (PR) program combined with inspiratory muscle training (IMT) or home-based IMT alone, in post lung transplantation patients, seems to be the best exercise combination for achieving the optimal effect, in inspiratory muscle strength and exercise capacity, with evidence for long-term benefits. Patients should be encouraged to participate in a PR program that includes home-based IMT exercise, especially in times of restricted mobility, as currently due to the COVID-19 pandemic.

Barak Pertzov,1,2 Maysaa Soliman,2 Yael Shostak,1,2 Moshe Heching,1,2 Dror Rosengarten,1,2 Gabriel Izbicki,3,4,* Mordechai Reuven Kramer1,2,* 1Pulmonary Division, Rabin Medical Center, Petach Tikva, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Pulmonary Institute, Shaare Zedek Medical Center, Jerusalem, Israel; 4Hebrew University-Hadassah Medical School, Jerusalem, Israel*These authors contributed equally to this workCorrespondence: Barak PertzovPulmonary Division, Rabin Medical Center, Petach Tikva, IsraelTel +972-3-9377221/3Fax +972-3-9242091Email pertzovb@gmail.comBackground: Lung volume reduction with endobronchial coils treatment (ECT), for patients with severe emphysema, has shown modest improvement in exercise capacity and lung functions in clinical trials, yet the benefit of this procedure is still unclear.Methods: We conducted a multicenter retrospective cohort study including all patients who underwent ECT in Israel and a propensity score matched control group of patients with chronic obstructive pulmonary disease (COPD) that were treated with usual care. The primary outcome was six-minute walk test distance (6MWTD), secondary outcomes were lung function tests and patient survival.Results: Overall, 46 patients were included in the ECT group. Their mean 6MWTD at baseline and at 6 and at 24 months post procedure was 331.0± 101.4, 372.9± 76.8 and 338.8± 104.8, respectively (overall P=0.04, pairwise comparison: baseline to 6 months (P=0.1), baseline to 24 months (P=1.0)). Mean FEV1 values at baseline and at 6 and at 24 months post procedure were 0.86± 0.38, 0.92± 0.37 and 0.82± 0.36 liters, respectively (overall P=0.003, pairwise comparison: baseline to 6 months (P=0.04), baseline to 24 months (P=0.75)). The median 6MWTD for the ECT and control groups at 24 months were 333.0 (262.5– 390) and 280 (210– 405), respectively (P=0.16). There was no difference in overall survival (P=0.84). Heterogenous emphysema was a significant predictor of treatment success in univariate analysis (p=0.004).Conclusion: Lung volume reduction with endobronchial coils may improve the exercise capacity and FEV1 of COPD patients. However, the majority of the effect was diminished after 24 months. The current state of evidence does not support regulatory approval of ECT and warrant its use only after consideration of the benefit-harm ratio in a highly selected patient population.Keywords: emphysema, endobronchial coils, lung volume reduction, six-minute walk, residual volume, FEV1, survival

Alpha 1 antitrypsin (A1AT) is the major human blood serine protease inhibitor. Transmembrane serine protease 2 (TMPRSS2), which is crucial for SARS-CoV-2 cell entry, is inhibited by A1AT. Therefore, we hypothesized that individuals with diminished levels of A1AT may be more prone to SARS-CoV-2 infection and severe COVID-19 disease. Our aim in this study was to evaluate the level of A1AT in hospitalized COVID-19 patients in comparison to hospitalized patients with non-COVID-19 pneumonia.We conducted an observational prospective study between October 2020 and April 2021 in Rabin Medical Centre in Israel. A1AT levels were measured from the routine serum samples of hospitalized patients with COVID-19 and non-COVID-19 pneumonia (control group). The primary outcome was A1AT level, secondary outcomes were clinical outcomes and predictors of morality.Overall, 145 patients were included in the study, 98 in the COVID-19 group and 47 in the control group. The median A1AT level was 222 mg/dL (interquartile range (IQR) 188-269) and 258 mg/dL (IQR 210-281) in the COVID-19 and control groups, respectively (Patients admitted due to severe COVID-19 had lower A1AT levels in comparison to patients admitted due to non-COVID pneumonia. This observation may suggest an association between mildly diminished A1AT and higher risk of SARS-CoV-2 infection with severe COVID-19 disease.

AIMS: To assess the short-term immunogenicity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in a population of heart transplant (HTx) recipients. A prospective single-centre cohort study of HTx recipients who received a two-dose SARS-CoV-2 mRNA vaccine (BNT162b2, Pfizer-BioNTech). METHODS AND RESULTS: Whole blood for anti-spike IgG (S-IgG) antibodies was drawn at days 21-26 and at days 35-40 after the first vaccine dose. Geometric mean titres (GMT) ≥50 AU/mL were interpreted positive. Included were 42 HTx recipients at a median age of 61 [interquartile range (IQR) 44-69] years. Median time from HTx to the first vaccine dose was 9.1 (IQR 2.6-14) years. Only 15% of HTx recipients demonstrated the presence of positive S-IgG antibody titres in response to the first vaccine dose [GMT 90 (IQR 54-229) AU/mL]. Overall, 49% of HTx recipients induced S-IgG antibodies in response to either the first or the full two-dose vaccine schedule [GMT 426 (IQR 106-884) AU/mL]. Older age [68 (IQR 59-70) years vs. 46 (IQR 34-63) years, P = 0.034] and anti-metabolite-based immunosuppression protocols (89% vs. 44%, P = 0.011) were associated with low immunogenicity. Importantly, 36% of HTx recipients who were non-responders to the first vaccine dose became S-IgG seropositive in response to the second vaccine dose. Approximately a half of HTx recipients did not generate S-IgG antibodies following SARS-CoV-2 two-dose vaccine. CONCLUSIONS: The generally achieved protection from SARS-CoV-2 mRNA vaccination should be regarded with caution in the population of HTx recipients. The possible benefit of additive vaccine should be further studied.

To compare the effectiveness of a combined aerobic, strength, and flexibility training program with flexibility alone on disease-specific and health-related symptoms in ambulatory amyotrophic lateral sclerosis (ALS) patients. Thirty-two ambulatory patients with ALS were equally randomized into a combined aerobic-strength intervention group or a stretching control group. The intervention period for both groups was identical, 12 consecutive weeks, two sessions per week. The combined intervention program consisted of aerobic training by recumbent cycling, flexibility achieved by stretching and passive exercises, and strength training via functional exercises. Patients in the control group performed basic stretching exercises of the upper and lower limb at home. Outcome measures included the ALS Functional Rating Scale-Revised (ALSFRS-R), respiratory function, mobility, fatigue, and quality of life and were collected 1-week prior to the intervention, after 6-weeks of training, and at the completion of the intervention. Twenty-eight participants (17 males, 11 females); mean age (S.D.) = 58.5 (13.2) years; mean disease duration (S.D.) = 7.3 (12.0) years, completed the study. According to the group X time analysis, significant differences were found in respiratory function, mobility, and the ALSFRS-R in favor of the aerobic-strength group. These patients maintained their abilities, whereas, a significant decrease was observed in the flexibility training group. Scores of the SF-36 categories “physical functioning”, “energy fatigue” and “wellbeing” were higher following the intervention in the aerobic-strength group compared with the stretching control group. A 12-week combined aerobic and strength training program is far superior to flexibility alone in improving respiratory function, mobility, and wellbeing in ambulatory ALS patients.

Background Central airway obstruction and fistula are treated with a tracheobronchial Y stent. In the currently used self‐expandable metal Y stents, the delivery system is 8 mm in diameter and requires either a 9 mm tracheal tube or rigid bronchoscope to enable airway control during insertion. In this study we present a novel technique of laryngeal mask airway (LMA) assisted Y stent insertion, enabling airway control during deployment of the Y stent. Methods All procedures using LMA in assisting Y stent insertions between 2014–2020 were reviewed. Data collected included demographics, clinical diagnosis and disease characteristics, indication, procedural success rates, clinical outcome and survival. Results A total of 10 patients with a median age of 61.5 years (range 37–73) underwent LMA assisted Y stent insertion. Indications for stent insertion were malignant disease with central airway obstruction or fistula. In all cases airway patency was achieved leading to improvement of symptoms and performance status. No procedural complications were reported. The median survival was 4.5 weeks (range: 2–26). Conclusions LMA assisted Y stent insertion enables airway control during the procedure. In comparison to silicone Y stent insertion, the procedure is less cumbersome, shorter in duration and does not require the use of general anesthesia or rigid bronchoscopy. Key points Significant findings of the study LMA assisted Y stent insertion enables airway control during the implantation of metallic self‐expanding Y stent. The procedure does not require the use of general anesthesia or rigid bronchoscopy. What this study adds In this study we present the technique and outcomes of LMA assisted Y stent insertion. This method of Y stent insertion provides an additional treatment option for patients with central airway obstruction and fistula., LMA assisted Y stent insertion enables airway control during the implantation of metallic self‐expanding Y stent. The procedure does not require the use of general anaesthesia or rigid bronchoscopy.

Polvo; Salud ocupacional; Pruebas de función respiratoria Dust; Occupational health; Respiratory function tests Pols; Salut ocupacional; Proves de funció respiratòria Objectives To investigate differences in workplace exposure, demographic and clinical findings in engineered stone (ES) workers from a multinational consortium using the Engineered Stone Silicosis Investigators (ESSI) Global Silicosis Registry. Methods With ethics board approval in Israel, Spain, Australia and the USA, ES workers ages 18+ with a physician diagnosis of work-related silicosis were enrolled. Demographic, occupational, radiologic, pulmonary function and silica-related comorbidity data were compared cross-sectionally among countries using analysis of variance, Fisher’s exact tests and logistic regression. Results Among 169 ES workers with silicosis, most were men, with mean age 51.7 (±11.4) years. Mean work tenure in stone fabrication or masonry was 19.9 (±9.8) years. Different methods of case ascertainment explained some inter-country differences, for example, workers in Queensland, Australia with a state-based surveillance program were likely to be identified earlier and with shorter work tenure. Overall, 32.5% of workers had progressive massive fibrosis, the most severe form of dust-related pneumoconiosis, of whom 18.5% reported ≤10 years of work tenure. Lung function impairment including restriction, reduced diffusion capacity and hypoxaemia was common, as was autoimmunity. Conclusions Findings from a multinational registry represent a unique effort to compare demographic, exposure and clinical information from ES workers with silicosis, and suggest a substantial emerging population of workers worldwide with severe and irreversible silica-associated diseases. This younger worker population is at high risk for disease progression, multiple comorbidities and severe disability. The ESSI registry provides an ongoing framework for investigating epidemiological trends and developing prospective studies for prevention and treatment of these workers. Work conducted at National Jewish Health was partially supported by the Reuben M Cherniack fellowship award. Work conducted in Israel was partially supported by the Committee for Research and Prevention in Occupational Safety and Health (56/13).

To identify predictors and evaluate outcomes of posttransplant diabetes mellitus (PTDM) and to investigate the effect of treatment modalities on outcomes. The database of a tertiary medical center was searched for all adult patients without prior diabetes who underwent lung, liver, or heart transplantation between January 1, 2012 and June 30, 2018. Patients in whom PTDM (defined as HbA1C ≥ 6.5% at least 3 months post transplantation) developed during follow-up (mean 3.32 years) were identified. Risk factors for PTDM, determined by regression analysis and clinical outcomes [all-cause mortality, severe infections, graft loss, and major adverse cardiovascular events (MACE)], were compared between those who developed PTDM and those who did not; in the former, insulin-based therapy was compared with non-insulin regimen. The cohort included 281 transplant recipients: 158 lung, 109 liver, and 14 heart. PTDM was diagnosed in 60 (21.35%) patients at a mean of 11.3 ± 12.89 months post transplantation. The only significant independent risk factor for PTDM was age (HR 1.028, 95% CI = 1.002–1.054, P = 0.0314). PTDM was associated with higher rates of severe infections (HR 2.565, 95% CI = 1.626–4.050, P

Background Lung transplantation is a life-saving treatment for patients with end stage lung disease. There may be a higher incidence of lung cancer in lung transplant recipients, and these cancers tend to be diagnosed at a more advanced stage. There is very little data on the safety and efficacy of stereotactic body radiation therapy (SBRT) for lesions in the native lung in lung-transplant recipients. Patients and methods A retrospective chart review of all patients who have undergone lung transplantation and were treated with SBRT for lung cancer in the native lung in the Davidoff Cancer Center was performed. Results Four patients who were treated with SBRT to a total of 5 lesions were included. Two patients were treated without histological confirmation of malignancy. All cases were discussed in a multidisciplinary tumor board before being referred for radiotherapy. Standard SBRT dosing was used. Responses were assessed by imaging. Three lesions exhibited a complete response and two lesions had a partial response. The patients who had partial responses developed distant metastases and died shortly. No patient developed measurable toxicity. Conclusions SBRT is effective and safe for the management of lung cancer in lung-transplant patients. Standard dose and fractionation can be used.

Background: Silicone gel-filled breast implants have been widely used for breast augmentation and reconstruction since the 1960’s when the FDA approved them in women over 22 years of age. Concerns have been raised about the safety of those implants, with the focus upon whether silicone leak can spread to regional lymph nodes and remote organs and possibly cause inflammatory and immune responses. Objective: To present laboratory workup findings in 3 cases of interstitial lung diseases (ILD) linked with silicone implant leakage. Methods: ILD was diagnosed by tissue biopsy and Computerized Tomography (CT). We analyzed the metal content in both biological samples and raw material of the implants by means of scanning electron microscopy (SEM) and X-ray fluorescence (XRF). The metals lymphocyte proliferation analysis (MELISA®) was used to assess sensitization of the immune system to 19 metals. Results: The biological samples contained metals (silicon, nickel, zinc, tungsten, iron, aluminum, and zirconium) which are also present in the silicone implant. The MELISA test showed sensitization to nickel, zinc and tin. Limitations: Some of the immunogenic metals present in the implant were under the limits of detection of SEM and XRF and the sensitivity of MELISA test is unknown. Conclusions: The laboratory assessments of the 3 herein described women indicated that their interstitial lung disease was associated with the metal content of their silicone gel-filled breast implantations. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 381-389)

Background Several registries of idiopathic pulmonary fibrosis (IPF) have been established to better understand its natural history, though their size and duration of follow-up are limited. Here, we describe the large European MultiPartner IPF Registry (EMPIRE) and validate predictors of long-term survival in IPF. Methods the multinational prospective EMPIRE registry enrolled IPF patients from 48 sites in 10 Central and Eastern European countries since 2014. Survival from IPF diagnosis until death was estimated, accounting for left-truncation. the Cox proportional hazards regression model was used to estimate adjusted hazard ratios (HR) of death for prognostic factors, using restricted cubic splines to fit continuous factors. Results the cohort included 1620 patients (mean age at diagnosis 67.6 years, 71% male, 63% smoking history), including 75% enrolled within 6 months of diagnosis. Median survival was 4.5 years, with 45% surviving 5 years post-diagnosis. Compared with GAP stage I, mortality was higher with GAP stages II (HR 2.9; 95% CI: 2.3-3.7) and III (HR 4.0; 95% CI: 2.8-5.7) while, with redefined cut-offs, the corresponding HRs were 2.7 (95% CI: 1.8-4.0) and 5.8 (95% CI: 4.0-8.3) respectively. Mortality was higher with concurrent pulmonary hypertension (HR 2.0; 95% CI: 1.5-2.9) and lung cancer (HR 2.6; 95% CI: 1.3-4.9). Conclusions EMPIRE, one of the largest long-term registries of patients with IPF, provides a more accurate confirmation of prognostic factors and co-morbidities on longer term five-year mortality. It also suggests that some fine-tuning of the indices for mortality may provide a more accurate long-term prognostic profile for these patients., Boehringer IngelheimBoehringer Ingelheim, The EMPIRE registry is supported by a grant from Boehringer Ingelheim (since 2014). the sponsor did not have any involvement in the collection, analysis, and interpretation of the data or in the writing of or commenting on this manuscript

Background Patients with interstitial lung disease (ILD) are at high risk of severe COVID-19 infection. Additionally, their anti-inflammatory and antifibrotic treatment may cause immunosuppression. Nevertheless, their ability to mount an adequate immune response to messenger RNA SARS-CoV-2 vaccines was not evaluated. Therefore, we aimed to evaluate the humoral response after the BNT162b2 vaccine among idiopathic pulmonary fibrosis (IPF) patients treated with antifibrotic therapy and among non-IPF ILD patients treated with anti-inflammatory therapy. Methods We conducted an observational prospective cohort study to evaluate the level of anti-spike (S-IgG) antibodies after two doses of the BNT162b2 vaccine in patients with ILD. The cohort included 40 patients with idiopathic pulmonary fibrosis (IPF) treated with anti-fibrotic therapy and 29 patients with non-IPF ILD treated with anti-inflammatory therapy. For S-IgG titer measurement, one serology test was drawn from all patients 4–6 months after the second vaccine dose. In addition a control group matched for age and sex was created from a healthy control cohort of 107 patients. The study was conducted in Rabin Medical Center (Israel) between June and August 2021. Results All patients in the anti-fibrotic arm were seropositive (40/40), corresponding to the matched control group (P = 1.0). The anti-fibrotic arm had a significantly lower median antibody titer in comparison to the matched control group (361.10 [IQR, 207–811] AU/ml vs. 820.75 [IQR, 459–1313] AU/ml; P Conclusion IPF patients treated with antifibrotic therapy mount an adequate immune response after 2 doses of the BNT162b2 vaccine, and maintain a 100% seropositivity rate 4–6 months after vaccination. However, their antibody titer was reduced in comparison to a healthy control group. Among patients with non-IPF ILD treated with anti-inflammatory therapy, 48% were seronegative 4–6 months after the second vaccine dose. Moreover, treatment with rituximab caused significant immunosuppression, even in comparison to other anti-inflammatory treatments.

Objectives Data are limited regarding the clinical significance of nontuberculous mycobacteria pulmonary infections among lung transplant recipients. We investigated the incidence and characteristics of pulmonary nontuberculous mycobacteria infection in ourlung transplant patient population. Materials and methods We obtaineddata of the patients who underwent lung transplant in our center from January 1997 to March 2019. Results Of 690 patients, nontuberculous mycobacteria were identified in 58 patients (8.4%) over a median follow-up of 3 years. Types of species were as follows: Mycobacterium simiae (n = 24), avium complex (n = 12), abscessus (n = 9), fortuitum (n = 6), chelonae (n = 2), szulgai (n = 1), kansasii (n = 1), lentiflavum (n = 1), and undefined mycobacteria (n = 2). When we compared infections in the early versus late period posttransplant (before and after 6 months), infections with Mycobacterium simiae (16 vs 8 incidents) and Mycobacterium fortuitum (5 vs 1 incident) were more often observed within the early period, whereas most Mycobacterium abscessus (7 vs 1 incident) and Mycobacterium avium complex (9 vs 3 incidents) were observed in the later period. The median forced expiratory volume in 1 second overtime did not differ significantly between patients with and without nontuberculous mycobacteria infection (P = .29). Nontuberculous mycobacteria acquisition was significantly associated with decreased survival (relative risk of 2.41, 95% CI, 1.70-3.43; P ⟨ .001). Conclusions The nontuberculous mycobacteria species isolated varied according to the time elapsed since transplant. Among lung transplant recipients, nontuberculous mycobacteria infection was associated with increased mortality but not with lung dysfunction.

Background Right heart catheterization (RHC) and echocardiography are both routinely used for pulmonary hypertension (PH) assessment in LT candidates, although this is not mandatory according to guidelines. We aim to describe the correlation between the pulmonary artery systolic pressure (PASP) measured by echocardiography to that measured by RHC in this population. Methods From a retrospective registry of 461 LT candidates, undergoing RHC between 2015–2019, 393 consecutive patients were assessed for the presence of pulmonary hypertension according to two methods – echocardiography and RHC. The primary outcome was the correlation between the estimated PASP measured by echocardiography to that measured by RHC. Secondary outcome was the accuracy of the echocardiographic assessment of PH. Results Patients were predominantly males (63.6%) with a mean age of 61.46±8.33y. The two most common etiologies for lung failure were interstitial lung disease or pulmonary fibrosis (52.2%) and chronic obstructive pulmonary disease (30.5%). Estimated PASP as measured by echocardiography was available in 89.31% of the patients, with a mean value of 49.5±20.02 mmHg. Mean PASP measured by RHC was 42.47±17.96 mmHg. The correlation between the two measurements was moderate (Pearson's correlation: r=0.609, p10 mmHg differences between the two values in 79.9% of the patients. Conclusions In the pre-surgical evaluation of LT candidates, echocardiographic estimation of PASP has moderate correlation with the PASP measured by RHC and relatively poor accuracy. Funding Acknowledgement Type of funding sources: None.

Background: The prognostic significance of amino-terminal pro-brain natriuretic peptide (NT-proBNP) in lung transplant candidates has not been investigated. Methods: The study was designed as a retrospective single-center investigation. Data regarding various baseline characteristics and all-cause mortality were collected in 172 lung transplant candidates placed in waiting list during November 2017−August 2018. The associations of NT-proBNP levels with baseline characteristics and mortality were analyzed. Results: NT-proBNP values correlated positively with age, forced vital capacity, mean pulmonary artery pressure (MPAP) and pulmonary capillary wedge pressure, while negatively with diffusing lung capacity for carbon monoxide and cardiac index. The optimal cut-off of NT-proBNP for prediction of MPAP levels ≥35 mmHg was 251 pg/ml; with 65.2% sensitivity, 89.3% specificity, 51.7% positive predictive value and 93.6% negative predictive value. On median follow-up period lasting 1.9 years, 81 patients underwent lung transplantation, 31 died waiting for donation, and 60 were alive and still waiting for the transplantation. There was a significantly higher risk of cumulative mortality in waitlisted lung transplant candidates with NT-proBNP level ≥450 vs.

Background There is no clear evidence whether pirfenidone has a benefit in patients with probable or possible UIP, i.e. when idiopathic pulmonary fibrosis (IPF) is diagnosed with a lower degree of diagnostic certainty. We report on outcomes of treatment with pirfenidone in IPF patients diagnosed with various degrees of certainty. Methods and findings We followed patients in the multi-national European MultiPartner IPF Registry (EMPIRE) first seen between 2015 and 2018. Patients were assessed with HRCT, histopathology and received a multi-disciplinary team (MDT) IPF diagnosis. Endpoints of interest were overall survival (OS), progression-free survival (PFS) and lung function decline. Results A total of 1626 patients were analysed, treated with either pirfenidone (N = 808) or receiving no antifibrotic treatment (N = 818). When patients treated with pirfenidone were compared to patients not receiving antifibrotic treatment, OS (one-, two- and three-year probability of survival 0.871 vs 0.798; 0.728 vs 0.632; 0.579 vs 0.556, P = 0.002), and PFS (one-, two- and three-year probability of survival 0.597 vs 0.536; 0.309 vs 0.281; 0.158 vs 0.148, P = 0.043) was higher, and FVC decline smaller (-0.073 l/yr vs -0.169 l/yr, P = 0.017). The benefit of pirfenidone on OS and PFS was also seen in patients with probable or possible IPF. Conclusions This EMPIRE analysis confirms the favourable outcomes observed for pirfenidone treatment in patients with definitive IPF and indicates benefits also for patients with probable or possible IPF., F. Hofmann-La Roche; Boehringer Ingelheim, This study was supported by F. Hofmann-La Roche. The EMPIRE registry is supported by Boehringer Ingelheim and F. Hofmann-La Roche. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Spectrophotometric techniques provide qualitative but not quantitative data on lung particles. We aimed to quantitate silica content in biopsies of lung-transplanted silicosis patients by applying X-ray fluorescence (XRF) spectrometry. Lung biopsies of 17 lung-transplanted artificial patients were quantitated for silica and other minerals particles by Niton XL3 XRF spectrometry. Occupational and clinical history data were assessed. Lung biopsies of artificial stone-induced silicosis (ASIS) patients contained significantly higher levels of silica compared to those of idiopathic pulmonary fibrosis (IPF) patients (7284.29 ± 4693.75 ppm vs. 898.88 ± 365.66 ppm, p &lt, 0.0001). Silica content correlated negatively with age, body mass index, and pulmonary function test results. A 1128 ppm silica cut-off value yielded 100% sensitivity and 94% specificity for predicting ASIS (AUC = 0.94, p &lt, 0.0001). In conclusion, XRF measurements in lung biopsies can differentiate between silica and mineral particles in ASIS and IPF.

Patients with COVID-19 report severe respiratory symptoms consistent with ARDS. The clinical presentation of ARDS in COVID-19 is often atypical, as patients with COVID-19 exhibit a disproportionate hypoxemia compared with relatively preserved lung mechanics. This pattern is more similar to neonatal respiratory distress syndrome secondary to surfactant deficiency, which has been shown to benefit from exogenous surfactant. We present our experience with exogenous surfactant treatment in a patient with COVID-19 experiencing COVID-19-related ARDS. The patient responded with improved oxygenation, and we believe surfactant was the catalyst for the successful extubation and clinical improvement of the patient.

ObjectiveArtificial stone dust (ASD) contains high levels of ultrafine particles (UFP Methods68 workers with up to 20 years of ASD exposure at the workplace were recruited from small enterprises throughout the country and compared with 48 non-exposed individuals. Pulmonary function test (PFT), CT, induced sputum (IS) and cytokine analyses were performed by conventional methods. The CT scans were evaluated for features indicative of silicosis in three zones of each lung. UFP were quantitated by the NanoSight LM20 system (NanoSight, Salisbury) using the Nanoparticle Tracking Analysis. Interleukin (IL)-6, IL-8 and tumour necrosis factor alpha (TNF-α) levels were measured by Luminex (R&D Systems).ResultsThirty-four patients had CT scores between 0 and 42, and 29 of them were diagnosed with silicosis. Content of the UFP retrieved from IS supernatants correlated negatively with the PFT results (total lung capacity r=−0.347, p=0.011; forced expiratory volume in 1 s r=−0.299, p=0.046; diffusion lung carbon monoxide in a single breath r=−0.425, p=0.004) and with the CT score (r=0.378, p=0.023), and with the inflammatory cytokines IL-8 (r=0.336, p=0.024), IL-6 (r=0.294, p=0.065) and TNF-α (r=0.409, p=0.007). Raw material of ASD was left to sedimentate in water for 6 UFP/mL in IS samples had a sensitivity of 77% to predict pulmonary disease.ConclusionsThis is the first demonstration of an association between UFP-related decreased PFT results, worsening of CT findings and elevation of inflammatory cytokines, which may be attributed to high-dose inhalation of UFP of ASD at the workplace.

The interleukin 5 (IL-5) pathway is an important component in the pathophysiology of severe eosinophilic asthma. Mepolizumab is a monoclonal antibody that targets the IL-5 pathway. Clinical trials showed efficacy of Mepolizumab in patients with severe eosinophilic asthma. However, reports on experience with treatment in a real-world cohort are limited.Evaluation of the efficacy and safety of Mepolizumab for treatment of severe eosinophilic asthma in a real-world cohort of patients.A clinical prospective observational trial included all patients18 years treated with Mepolizumab between March 2016 to March 2019 at Rabin Medical Center. The composite primary outcome measures evaluated: increase in FEV1 by≥ 200 ml and/or decrease in exacerbation rate of ≥50% and/or cessation of oral corticosteroids (OCS) treatment or ≥50% decrease in dosage. Also evaluated: blood eosinophil count, adverse events and quality of life.Of 61 patients, 50 (82.0%) achieved the primary outcome. The number of patients who suffered from frequent exacerbations decreased from 52 (85.2%) to 8 (13.1%) (Treatment with mepolizumab was well tolerated and significantly lowered the exacerbation rate and OCS dependence in a real-world cohort of severe eosinophilic asthma patients. Response to therapy was within six months and treatment effect was sustained over time.

Introduction Advanced non-small cell lung cancer (NSCLC) is still a therapeutic challenge as the 5-year survival is under 30%. The optimal treatment regimen is still under debate. Hypothesis Neo adjuvant (NA) treatment given pre-pneumonectomy does not increase surgical complexity or peri-OP mortality while it has a potential to increase long term survival. Methods We have conducted a retrospective study of 169 patients who underwent a pneumonectomy for NSCLC between January 2005 to December 2015 and focused on stage IIIa patients; a cohort of 51 patients, 30 which received neo adjuvant chemo-radiation (NA group) prior to pneumonectomy and 21 patients who had undergone pneumonectomy followed by adjuvant treatment (Adjuvant group). Surgical complexity and short- and long-term survival were evaluated. Surgical complexity was assessed by surrogates as surgery duration, hospitalization length and interdepartmental transfer. Results While no statistically significant differences were found in surgery duration, hospitalization length, morbidity in the 1st year post-OP and the peri-OP mortality; The long term beneficiary effect among the neo adjuvant patients was clear; while 30% of the NA patients were alive 8 years post-OP, there were no survivors in the adjuvant group 5.5 years post-OP. Conclusion We conclude that while NA treatment has no effect on operation complexity, peri-OP mortality or post-OP morbidity; its impact on long term survival is protuberant, therefore, we believe that NA treatment should be considered as the treatment of choice in advanced NSCLC in need for pneumonectomy.

Background Capnography waveform contains essential information regarding physiological characteristics of the airway and thus indicative of the level of airway obstruction. Our aim was to develop a capnography-based, point-of-care tool that can estimate the level of obstruction in patients with asthma and COPD. Methods Two prospective observational studies conducted between September 2016 and May 2018 at Rabin Medical Center, Israel, included healthy, asthma and COPD patient groups. Each patient underwent spirometry test and continuous capnography, as part of, either methacholine challenge test for asthma diagnosis or bronchodilator reversibility test for asthma and COPD routine evaluation. Continuous capnography signal, divided into single breaths waveforms, were analyzed to identify waveform features, to create a predictive model for FEV1 using an artificial neural network. The gold standard for comparison was FEV1 measured with spirometry. Measurements and main results Overall 160 patients analyzed. Model prediction included 32/88 waveform features and three demographic features (age, gender and height). The model showed excellent correlation with FEV1 (R = 0.84), R2 achieved was 0.7 with mean square error of 0.13. Conclusion In this study we have developed a model to evaluate FEV1 in asthma and COPD patients. Using this model, as a point-of-care tool, we can evaluate the airway obstruction level without reliance on patient cooperation. Moreover, continuous FEV1 monitoring can identify disease fluctuations, response to treatment and guide therapy. Trial registration clinical trials.gov, NCT02805114. Registered 17 June 2016, https://clinicaltrials.gov/ct2/show/NCT02805114

Background The LungVision system is a novel augmented‐fluoroscopy‐based real‐time navigation and guidance technology for bronchoscopy that can be integrated with any standard biopsy tool, including the cryoprobe, to enable real‐time visualization and localization of pulmonary nodules. Objectives To evaluate the diagnostic yield and safety among patients undergoing peripheral pulmonary nodule biopsy with the LungVision system. Methods This prospective, single‐center study was conducted at Rabin Medical Center in Israel. All patients that underwent peripheral pulmonary nodule biopsy with the LungVision system from January 2016 to August 2020 were included. All procedures were performed under moderate sedation. The primary outcome was tissue diagnosis by either identification of malignant cells or benign diagnosis. Secondary outcomes were safety and the added value of cryobiopsy. Results Sixty‐three procedures were performed during the study period. Median lesion size (interquartile range) was 25.0 mm (18–28 mm). The diagnostic yield overall was 27/33 (81.8%) and for lesions smaller than 20 mm was 13/18 (72.2%). In nine cases the transbronchial cryobiopsy showed tissue with malignant cells that were not found in any other biopsy material taken with other sampling tools. One patient was treated with a chest tube for a pneumothorax. No other major complications were reported. Conclusions The LungVision system showed good feasibility and safety for peripheral pulmonary nodule biopsy. The system is compatible with all biopsy tools, including the cryoprobe. Randomized controlled trials are needed to accurately ascertain its diagnostic yield., The LungVision fluoroscopy‐based navigation and guidance technology for bronchoscopic biopsy of peripheral pulmonary nodules is safe and effective.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix–fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH4OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of ‘HIF1α signaling pathway’ (KEGG, p &lt, 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib.

Background: A correlation of adverse events (AE), and the efficacy of EGFR TKIs in lung cancer patients (pts) is known. Similar AE are seen in IPF pts treated with triple TKI nintedanib (N) and pirfenidone (P). Post hoc analysis to assess the correlation between clinically outcomes in IPF pts from the real-world EMPIRE registry and AE to antifibrotics. Methods The analysis was performed 6 months after the initiation of antifibrotics according to AE. Correlation with mortality and progression-free survival-PFS, were assessed by the Kaplan–Meier survival function, correlation with AE by the Cox proportional hazards regression analysis. Results: Out of 1,233 pts, 698 were treated with P and 535 with N; AE were observed in 96 pts (7.8%): dyspepsia in 2.1%, elevated liver enzymes in 1.6%, diarrhoea in 0.7%, nausea in 1.1%, photosensitivity,rash,vomiting in 0.3% each, fatigue in 0.2%. The occurrence of AE correlated with the PFS, for all pts (p= 0.004) and for treated with N (p= 0.015), but not mortality. PFS was significantly better in the group of pts with no AE. Fatigue in all pts (adjusted HR 6.0; 1.5–24.8;p= 0.012), in treated with P(5.0; 1.2–20.5;p= 0.027), nausea in pts with N (6.8;1.6–28.8;p= 0.010) correlated with higher mortality. The effect of AE on PFS were noted in all pts for nausea (2.2; 1.2–3.8; p= 0.006) and rash (4.1;1.5–11.0;p= 0.005); in pts on P for rash (4.2;1.5–11.2;p= 0.005);in pts on N for nausea (3.5;1.6–7.5; p= 0.001). Conclusion: The occurrence of AE correlates with PFS, but not with mortality. The occurrence of individual AE is associated with a poorer prognosis of pts.

Background: Malignancy after lung transplantation is an important cause of morbidity and mortality and is associated with the intensity and cumulative dose of immunosuppressive drugs. There is some evidence that the use of mammalian target of rapamycin (mTOR) inhibitors may reduce the risk of malignancy in kidney transplant recipients. Aims: To compare the effect of everolimus on the incidence of new malignancies, as well as the rate of acute rejection, CMV infection and overall survival between lung transplant recipients who were treated with an everolimus/calcineurin inhibitors (CNI)-based regimen versus CNI-based regimen. Methods: A single center retrospective cohort study including all transplanted patients treated with everolimus for >7 months from 1998-2019. Propensity score matching was used to select a similar control group. Results: 142 lung transplant recipients and matched controls were included. The incidence of malignancies was not significantly different between groups (RR 0.75, CI 0.34-1.67, P=0.48). However, a survival benefit was demonstrated in the everolimus group compared to the control group. In addition, the rate of acute rejection events was lower in the everolimus group (RR 0.31, CI 0.15-0.63, P=0.001). There were also less CMV infection episodes in the everolimus group (8.4%) compared to the control group (16.9%) (P=0.07). Conclusions: Whereas our study did not show a significant difference in the incidence of malignancies among the two groups of lung transplant recipients, our results suggest that treatment with everolimus may prolong survival and decrease the rates of acute rejection and CMV infection episodes.