Search

Barbara Dymek,1,2 Piotr Sklepkiewicz,1 Michal Mlacki,1 Nazan Cemre Güner,1 Patrycja Nejman-Gryz,3 Katarzyna Drzewicka,1 Natalia Przysucha,3 Aleksandra Rymaszewska,1 Magdalena Paplinska-Goryca,3 Agnieszka Zagozdzon,1 Małgorzata Proboszcz,3 Łukasz Krzemiński,1 Jan H von der Thüsen,4 Katarzyna Górska,3 Karolina Dzwonek,1 Zbigniew Zasłona,1 Pawel Dobrzanski,1 Rafał Krenke3 1Molecure SA, Warsaw, 02-089, Poland; 2Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, 02-097, Poland; 3Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, 02-097, Poland; 4Department of Pathology, Erasmus Medical Center, Rotterdam, 3015 GD, the NetherlandsCorrespondence: Barbara Dymek, Żwirki i Wigury 101, Warsaw, 02-089, Poland, Tel +48 22 552 67 24, Email b.dymek@molecure.comIntroduction: Sarcoidosis is a systemic disease of unknown etiology characterized by granuloma formation in the affected tissues. The pathologically activated macrophages are causatively implicated in disease pathogenesis and play important role in granuloma formation. Chitotriosidase (CHIT1), macrophage-derived protein, is upregulated in sarcoidosis and its levels correlate with disease severity implicating CHIT1 in pathology.Methods: CHIT1 was evaluated in serum and bronchial mucosa and mediastinal lymph nodes specimens from sarcoidosis patients. The therapeutic efficacy of OATD-01 was assessed ex vivo on human bronchoalveolar lavage fluid (BALF) macrophages and in vivo in the murine models of granulomatous inflammation.Results: CHIT1 activity was significantly upregulated in serum from sarcoidosis patients. CHIT1 expression was restricted to granulomas and localized in macrophages. Ex vivo OATD-01 inhibited pro-inflammatory mediators’ production (CCL4, IL-15) by lung macrophages. In the acute model of granulomatous inflammation in mice, OATD-01 showed anti-inflammatory effects reducing the percentage of neutrophils and CCL4 concentration in BALF. In the chronic model, inhibition of CHIT1 led to a decrease in the number of organized lung granulomas and the expression of sarcoidosis-associated genes.Conclusion: In summary, CHIT1 activity was increased in sarcoidosis patients and OATD-01, a first-in-class CHIT1 inhibitor, demonstrated efficacy in murine models of granulomatous inflammation providing a proof-of-concept for its clinical evaluation in sarcoidosis.Keywords: chitinase, OATD-01, granuloma, macrophages, interstitial lung disease

The strain Gluconobacter oxydans LMG 1385 was used for the bioconversion of crude glycerol to dihydroxyacetone. The suitability of fed-batch cultures for the production of dihydroxyacetone was determined, and the influence of the pH of the culture medium and the initial concentration of glycerol on maximizing the concentration of dihydroxyacetone and on the yield and speed of obtaining dihydroxyacetone by bioconversion was examined. The feeding strategy of the substrate (crude glycerol) during the process was based on measuring the dissolved oxygen tension of the culture medium. The highest concentration of dihydroxyacetone P K = 175.8 g·L -1 and the highest yield Y P/Sw = 94.3% were obtained when the initial concentration of crude glycerol was S 0 = 70.0 g·L -1 and the pH of the substrate was maintained during the process at level 5.0.

COPD is the third leading cause of death worldwide. Its diagnosis can be made with spirometry, which is underused due to its limited accessibility. Portable spirometry holds promise for enhancing the efficacy of COPD diagnoses. The study aimed to estimate COPD prevalence diagnosed with a portable spirometer in high-risk patients and compare it with COPD prevalence based on data from conventional, on-site spirometry. We also evaluated the strategy of a proactive approach to identify COPD in high-risk individuals. We conducted a systematic review of original studies on COPD targeted screening and diagnosis with portable and conventional spirometers selected from 8496 publications initially found in three databases: Cochrane, PubMed, and Embase. The inclusion criteria were met by 28 studies. COPD prevalence evaluated with the use of portable spirometers reached 20.27% and was lower compared to that estimated with the use of conventional spirometers (24.67%). In 11 included studies, postbronchodilator tests were performed with portable spirometers, which enabled a bedside COPD diagnosis. Portable spirometers can be successfully used in COPD targeted screening and diagnosis and thus enhance the detection of COPD at early stages.

Background: The COVID-19 pandemic has constrained access to spirometry, and the inherent risk of infectious transmission during aerosol-generating procedures has necessitated the rapid development of Remotely Supervised Spirometry (RSS). This innovative approach enables patients to perform spirometry tests at home, using a mobile connected spirometer, all under the real-time supervision of a technician through an online audio or video call., Methods: In this retrospective study, we examined the quality of RSS in comparison to conventional Laboratory-based Spirometry (LS), using the same device and technician. Our sample included 242 patients, with 129 undergoing RSS and 113 participating in LS. The RSS group comprised 51 females (39.5%) with a median age of 37 years (range: 13-76 years). The LS group included 63 females (55.8%) with a median age of 36 years (range: 12-80 years)., Results: When comparing the RSS group to the LS group, the percentage of accurate Forced Expiratory Volume in one second (FEV1) measurements was 78% (n = 101) vs. 86% (n = 97), p = 0.177; for Forced Vital Capacity (FVC) it was 77% (n = 99) vs. 82% (n = 93), p = 0.365; and for both FEV1 and FVC, it was 75% (n = 97) vs. 81% (n = 92), p = 0.312, respectively., Conclusions: Our findings demonstrate no significant difference in the quality of spirometry testing between RSS and LS, a result that held true across all age groups, including patients aged over 65 years. The principal advantages of remote spirometry include improved access to pulmonary function tests, reduced infectious risk to curtail disease spread, and enhanced convenience for patients., (© 2024. The Author(s).)

Objective . The quality of spirometry manoeuvres is crucial for correctly interpreting the values of spirometry parameters. A fundamental guideline for proper quality assessment is the American Thoracic Society and European Respiratory Society (ATS/ERS) Standards for spirometry, updated in 2019, which describe several start-of-test and end-of-test criteria which can be assessed automatically. However, the spirometry standards also require a visual evaluation of the spirometry curve to determine the spirograms' acceptability or usability. In this study, we present an automatic algorithm based on a convolutional neural network (CNN) for quality assessment of the spirometry curves as an alternative to manual verification performed by specialists. Approach . The algorithm for automatic assessment of spirometry measurements was created using a set of randomly selected 1998 spirograms which met all quantitative criteria defined by ATS/ERS Standards. Each spirogram was annotated as 'confirm' (remaining acceptable or usable status) or 'reject' (change the status to unacceptable) by four pulmonologists, separately for FEV1 and FVC parameters. The database was split into a training (80%) and test set (20%) for developing the CNN classification algorithm. The algorithm was optimised using a cross-validation method. Main results . The accuracy, sensitivity and specificity obtained for the algorithm were 92.6%, 93.1% and 90.0% for FEV1 and 94.1%, 95.6% and 88.3% for FVC, respectively. Significance. The algorithm provides an opportunity to significantly improve the quality of spirometry tests, especially during unsupervised spirometry. It can also serve as an additional tool in clinical trials to quickly assess the quality of a large group of tests., (Creative Commons Attribution license.)

Nintedanib is a disease-modifying agent licensed for the treatment of IPF. Data on Polish experience with nintedanib in IPF are lacking. The present study aimed to describe the safety and efficacy profiles of nintedanib in a large real-world cohort of Polish patients with IPF. This was a multicenter, retrospective, observational study of IPF patients treated with nintedanib between March 2018 and October 2021. Data collection included baseline clinical characteristics, results of pulmonary function tests (PFTs), and a six-minute walk test (6MWT). Longitudinal data on PFTs, 6MWT, adverse drug reactions (ADRs), and treatment persistence were also retrieved. A total of 501 patients (70% male) with a median age of 70.9 years (IQR 65-75.7) were included in this study. Patients were followed on treatment for a median of 15 months (7-25.5). The majority of patients (66.7%) were treated with the full recommended dose of nintedanib and 33.3% of patients were treated with a reduced dose of a drug. Intermittent dose reductions or drug interruptions were needed in 20% of patients. Over up to 3 years of follow-up, pulmonary function remained largely stable with the minority experiencing disease progression. The most frequent ADRs included diarrhea (45.3%), decreased appetite (29.9%), abdominal discomfort (29.5%), weight loss (32.1%), nausea (20.8%), fatigue (19.2%), increased liver aminotransferases (15.4%), and vomiting (8.2%). A total of 203 patients (40.5%) discontinued nintedanib treatment due to diverse reasons including ADRs (10.2%), death (11.6%), disease progression (4.6%), patient's request (6.6%), and neoplastic disease (2.2%). This real-world study of a large cohort of Polish patients with IPF demonstrates that nintedanib therapy is safe, and is associated with acceptable tolerance and disease stabilization. These data support the findings of previously conducted clinical trials and observational studies on the safety and efficacy profiles of nintedanib in IPF.

Different eosinophil subpopulations have been identified in asthma and other eosinophilic disorders. However, there is a paucity of data on eosinophil subpopulations in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to compare eosinophil phenotypes in blood and induced sputum in patients with COPD, asthma and controls. Stable patients with mild-to-moderate COPD ( n = 15) and asthma ( n = 14) with documented blood eosinophilia ≥100 cells/µL in the year prior to the study and the control group ( n = 11) were included to the study. The blood and sputum eosinophil phenotypes were analyzed by flow cytometry. IL-5, IL-13, CCL5 and eotaxin-3 levels were measured in the induced sputum. The marker expression on blood eosinophils was similar among control, asthma and COPD groups. The expressions of CD125, CD193, CD14 and CD62L were higher on blood than on sputum eosinophils in all three groups. We found increased levels of CD193+ and CD66b+ sputum eosinophils from COPD patients, and an elevated level of CD11b+ sputum eosinophils in asthma compared to COPD patients. The results of our study suggest that the profile of marker expression on COPD sputum eosinophils differed from other groups, suggesting a distinct phenotype of eosinophils of COPD patients than in asthma or healthy subjects.

Chronic obstructive pulmonary disease (COPD), as the third leading cause of death among adults, is a significant public health problem around the world. However, about 75% of smokers do not develop the disease despite the severe smoking burden. COPD is a heterogeneous disease, and several phenotypes, with differences in their clinical picture and response to treatment, have been distinguished. Metabolomic studies provide information on metabolic pathways, and therefore are a promising tool for understanding disease etiopathogenesis and the development of effective causal treatment. The aim of this systematic review was to analyze the metabolome of the respiratory epithelial lining fluid of patients with COPD, compared to healthy volunteers, refractory smokers, and subjects with other lung diseases. We included observational human studies. Sphingolipids, phosphatidylethanolamines, and sphingomyelins distinguished COPD from non-smokers; volatile organic compounds, lipids, and amino acids distinguished COPD from smokers without the disease. Five volatile organic compounds were correlated with eosinophilia and four were associated with a phenotype with frequent exacerbations. Fatty acids and ornithine metabolism were correlated with the severity of COPD. Metabolomics, by searching for biomarkers and distinguishing metabolic pathways, can allow us to understand the pathophysiology of COPD and the development of its phenotypes.

Chitinases and chitinase-like proteins are thought to play a role in innate inflammatory responses. Our study aimed to assess whether chitinase concentration and activity in induced sputum (IS) of patients exposed to tobacco smoke are related to the level of airway inflammation including the level and activity of chitinases and chitinase-like proteins. The study included 22 patients with chronic obstructive pulmonary disease (COPD), 12 non-COPD smokers, and nine nonsmoking subjects. Sputum CHIT1 and YKL-40 levels and chitinolytic activity were compared with sputum IL-6, IL-8, IL-18, and MMP-9 levels. A hierarchical cluster analysis was also performed. Sputum YKL-40 was higher in COPD patients than in the control groups. Sputum CHIT1 and YKL-40 levels correlated with IS inflammatory cell count as well as with MMP-9 and IL-8 levels. Two main clusters were revealed: Cluster 1 had lower chitinase levels and activity, lower IS macrophage and neutrophil count, and lower IS IL-8, IL-18, and MMP-9 than Cluster 2. Comparison of COPD patients from both clusters revealed significant differences in the IS inflammatory profile despite comparable clinical and functional data. Our findings seem to confirm the involvement of chitinases in smoking-associated chronic airway inflammation and show that airway chitinases may be a potential novel marker in COPD phenotyping.

Background: Pirfenidone and nintedanib are considered as the standard of care in idiopathic pulmonary fibrosis (IPF), but there is no consensus as to which of these two agents should be regarded as first-line treatment., Objective: To provide real-world data on therapeutic decisions of pulmonary specialists, particularly the choice of the antifibrotic drug in patients with IPF., Methods: This was a multicenter, prospective survey collecting clinical data of patients with IPF considered as candidates for antifibrotic treatment between September 2019 and December 2020. Clinical characteristics and information on the therapeutic approach were retrieved. Statistical evaluation included multiple logistic regression analysis with stepwise model selection., Results: Data on 188 patients [74.5% male, median age 73 (interquartile range, 68-78) years] considered for antifibrotic therapy were collected. Treatment was initiated in 138 patients, while 50 patients did not receive an antifibrotic, mainly due to the lack of consent for treatment and IPF severity. Seventy-two patients received pirfenidone and 66 received nintedanib. Dosing protocol ( p  < 0.01) and patient preference ( p  = 0.049) were more frequently associated with the choice of nintedanib, while comorbidity profile ( p  = 0.0003) and concomitant medication use ( p  = 0.03) were more frequently associated with the choice of pirfenidone. Age ( p  = 0.002), lung transfer factor for carbon monoxide (TL CO ) ( p  = 0.001), and gastrointestinal bleeding ( p  = 0.03) were significantly associated with the qualification for the antifibrotic treatment., Conclusion: This real-world prospective study showed that dose protocol and patient preference were more frequently associated with the choice of nintedanib, while the comorbidity profile and concomitant medication use were more frequently associated with the choice of pirfenidone. Age, TL CO , and history of gastrointestinal bleeding were significant factors influencing the decision to initiate antifibrotic therapy., Competing Interests: Competing interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Honoraria for lectures; payment to Author Support for attending meetings and/or travel – fee, travel, and accommodation. K.G. and M.M.-W. report honoraria for lectures by Roche and Boehringer Ingelheim, support for attending meetings and travel by Roche and Boehringer Ingelheim and participation in Advisory Boards by Boehringer Ingelheim, outside the submitted work; M.B. reports honoraria for lectures by Chiesi Pharmaceuticals GmbH, Roche and Boehringer Ingelheim. A.Bi. reports honoraria for lectures, payment for expert testimony and support for attending meetings and travel by Chiesi Poland; A.Ba. reports support for attending meetings and travel by Boehringer Ingelheim and participation in Advisory Boards by Boehringer Ingelheim; H.J.-L. reports honoraria for lectures, receipt of equipment, materials, drugs, medical writing, gifts and other services and support for attending meetings and travel by Roche and Boehringer Ingelheim; E.J. reports honoraria for lectures by Roche and Boehringer Ingelheim, support for attending meetings and travel by Roche and Boehringer Ingelheim and participation in Advisory Boards by Roche and Boehringer Ingelheim, outside the submitted work; A.K. reports honoraria for lectures by Roche and Boehringer Ingelheim, support for attending meetings and travel by Boehringer Ingelheim, outside the submitted work; K.L. reports honoraria for lectures and supports for attending meetings and travels by Roche and Boehringer Ingelheim and declares participation on an advisory board by Boehringer Ingelheim and patients’ advocacy advisory board by Roche, she reports the role as a leadership or fiduciary role in EU-IPFF Scientific Committee and in Polish IPF Patients’ Support Society; S.M. and W.J.P. report consulting fees, honoraria for lectures, support for attending meetings and travel by Boehringer Ingelheim and participation in Boehringer Ingelheim’s Advisory Boards, outside the submitted work; M.M.-B. has nothing to disclose; A.S. reports honoraria for lectures by Roche and Boehringer Ingelheim, support for attending meetings and travel by Roche and Boehringer Ingelheim; K.S. has nothing to disclose. M.S. reports honoraria for lectures by Roche and Boehringer Ingelheim, support for attending meetings and travel by Roche and Boehringer Ingelheim and participation in Advisory Boards by Boehringer Ingelheim and reports the role as a member of the Audit Committee in Polish IPF Patients’ Support Society; M.T-S. and W.T. have nothing to disclose; B.Ż. reports support for attending meetings and travel by Roche, Boehringer Ingelheim, Chiesi Pharmaceuticals GmbH; R.K. reports support for attending meetings and travel by Boehringer Ingelheim and participation in Advisory Boards for MSD, outside the submitted work., (© The Author(s), 2022.)

Background: Ambulophobia is a type of specific phobia that involves a fear of walking. This phobia mainly affects older people, who prefer not to leave their bed or home to avoid walking on uneven surfaces and reduce the risk of falling. The problem seems to be very important in terms of public health and the organization of long-term care, as Poland has one of the highest rates of elderly population growth., Objectives: The aim of the study was to determine the prevalence of ambulophobia among patients of long-term care facilities in Poland and to identify factors increasing the risk of this specific phobia in the study group., Material and Methods: The study was conducted between January and July 2021. Data collected from 379 patients of 16 long-term care facilities located in Poland were analyzed. The study used the diagnostic criteria for specific phobias according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, and standardized questionnaires such as MMSE, GDS-16, DOS and ADL. The χ 2 test was used to test the significance of differences ( p = 0.05)., Results: The prevalence of ambulophobia in the study group was 30.1%. Ambulophobia significantly more often concerned the female sex (37.7%) and people over 70 years of age (42,1%). Factors such as depression, Parkinson's disease, orthostatic hypotonia, a history of falling or being a witness to another person falling, and disability of at least a moderate degree increased the likelihood of ambulophobia., Conclusions: Based on the obtained results, it was found that the protective factors in the development of ambulophobia are male sex, younger age, high independence, fewer drugs used per day and no previous falls or seeing another person fall., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Górski, Buczkowska, Krzywkowska, Całyniuk, Górska, Buczkowski, Fojcik, Grajek and Polaniak.)

Idiopathic pulmonary fibrosis (IPF) is a progressive and eventually fatal lung disease with a complex etiology. Approved drugs, nintedanib and pirfenidone, modify disease progression, but IPF remains incurable and there is an urgent need for new therapies. We identified chitotriosidase (CHIT1) as new driver of fibrosis in IPF and a novel therapeutic target. We demonstrate that CHIT1 activity and expression are significantly increased in serum (3-fold) and induced sputum (4-fold) from IPF patients. In the lungs CHIT1 is expressed in a distinct subpopulation of profibrotic, disease-specific macrophages, which are only present in patients with ILDs and CHIT1 is one of the defining markers of this fibrosis-associated gene cluster. To define CHIT1 role in fibrosis, we used the therapeutic protocol of the bleomycin-induced pulmonary fibrosis mouse model. We demonstrate that in the context of chitinase induction and the macrophage-specific expression of CHIT1, this model recapitulates lung fibrosis in ILDs. Genetic inactivation of Chit1 attenuated bleomycin-induced fibrosis (decreasing the Ashcroft scoring by 28%) and decreased expression of profibrotic factors in lung tissues. Pharmacological inhibition of chitinases by OATD-01 reduced fibrosis and soluble collagen concentration. OATD-01 exhibited anti-fibrotic activity comparable to pirfenidone resulting in the reduction of the Ashcroft score by 32% and 31%, respectively. These studies provide a preclinical proof-of-concept for the antifibrotic effects of OATD-01 and establish CHIT1 as a potential new therapeutic target for IPF., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Mobile phone-linked portable spirometers are light-weight, easy to use and low cost, with new software to facilitate data collection. In this study we investigated the feasibility of the AioCare® mobile spirometry in primary care., Methods: In this nationwide, cross-sectional study, AioCare® spirometers (HealthUp, Poland) were distributed among primary healthcare centres across Poland. Operators (primary care professionals) received a 2-h training session, after which spirometry was performed in patients attending routine visits with respiratory symptoms or risk factors for obstructive airway diseases. Spirometry was considered technically correct when at least three manoeuvres met ERS/ATS acceptability and repeatability criteria. The most common spirometry errors were assessed and stepwise logistic regression was applied to identify factors associated with technically correct spirometry. Airway obstruction was defined as FEV 1 /FVC below the lower limit of normal. A restrictive pattern was defined as FVC below the lower limit of normal., Results: Between 1 September 2018 and 1 September 2019, 10,936 spirometry examinations were performed in 9855 patients by 673 operators. 5347 (49%) spirometry examinations met both acceptability and repeatability criteria. The most common error was plateau error (17.7%). Operator age >40 years (OR 1.49, 95% CI 1.35-1.64) and repetition of the examination at the same visit (OR 1.90, 95% CI 1.66-2.16) increased the likelihood of a technically correct examination. Airway obstruction was found in 17% of correctly performed spirometry examinations., Conclusions: Our nationwide study suggests that use of the AioCare® mobile spirometer in primary care could be feasible. More intensive and continual training should be implemented to improve the quality of spirometry examinations., (Copyright © 2021 Elsevier Ltd. All rights reserved.)