The accuracy of electromagnetic navigation bronchoscopy compared to fluoroscopy in navigation of transbronchial lung cryobiopsy in patients with interstitial lung disease.

BACKGROUND: Safely implementing transbronchial lung cryobiopsy (TBLC) in patients with interstitial lung disease (ILD) requires accurate navigation. Traditional fluoroscopy falls short in reducing the risk of post-procedure pneumothorax. The potential of electromagnetic navigation bronchoscopy (ENB) as a more precise navigation method warrants further exploration. METHODS: A prospective cohort study was conducted on ILD patients undergoing TBLC. Patients were assigned either fluoroscopy or ENB for cryoprobe positioning. Navigation accuracy was evaluated using cone beam computed tomography (CBCT) images as the standard. Safety and diagnostic yield were also observed. RESULTS: Seventeen patients underwent TBLC, with 10 guided by fluoroscopy and seven by ENB. Fluoroscopy-guided cryoprobe navigation required more adjustments [9/15 (60%) v.s. 1/9 (11%), p = 0.018] for subsequent TBLC compared to ENB, as confirmed by CBCT images. Clinical characteristics, post-procedure complications, and biopsy specimen size showed no significant differences between the groups. Fourteen patients obtained a pathological diagnosis, and 15 received a multidisciplinary discussion (MDD) diagnosis. In the fluoroscopy group, three patients failed to obtain a pathological diagnosis, and two failed to obtain an MDD diagnosis. CONCLUSIONS: ENB demonstrates significantly superior accuracy in TBLC navigation compared to traditional fluoroscopy when CBCT images are used as a reference. Further studies are necessary to determine the value of ENB in TBLC navigation for ILD patients.

Elastic Registration Algorithm Based on Three-dimensional Pulmonary MRI in Quantitative Assessment of Severity of Idiopathic Pulmonary Fibrosis.

PURPOSE: To quantitatively analyze lung elasticity in idiopathic pulmonary fibrosis (IPF) using elastic registration based on 3-dimensional pulmonary magnetic resonance imaging (3D-PMRI) and to assess its' correlations with the severity of IPF patients. MATERIAL AND METHODS: Thirty male patients with IPF (mean age: 62±6 y) and 30 age-matched male healthy controls (mean age: 62±6 y) were prospectively enrolled. 3D-PMRI was acquired with a 3-dimensional ultrashort echo time sequence in end-inspiration and end-expiration. MR images were registered from end-inspiration to end-expiration with the elastic registration algorithm. Jacobian determinants were calculated from deformation fields on color maps. The log means of the Jacobian determinants (Jac-mean) and Dice similarity coefficient were used to describe lung elasticity between 2 groups. Then, the correlation of lung elasticity with dyspnea Medical Research Council (MRC) score, exercise tolerance, health-related quality of life, lung function, and the extent of pulmonary fibrosis on chest computed tomography were analyzed. RESULTS: The Jac-mean of IPF patients (-0.19, [IQR: -0.22, -0.15]) decreased (absolute value), compared with healthy controls (-0.28, [IQR: -0.31, -0.24], P<0.001). The lung elasticity in IPF patients with dyspnea MRC≥3 (Jac-mean: -0.15; Dice: 0.06) was significantly lower than MRC 1 (Jac-mean: -0.22, P=0.001; Dice: 0.10, P=0.001) and MRC 2 (Jac-mean: -0.21, P=0.007; Dice: 0.09, P<0.001). In addition, the Jac-mean negatively correlated with forced vital capacity % (r=-0.487, P<0.001), forced expiratory volume 1% (r=-0.413, P=0.004), TLC% (r=-0.488, P<0.001), diffusing capacity of the lungs for carbon monoxide % predicted (r=-0.555, P<0.001), 6-minute walk distance (r=-0.441, P=0.030) and positively correlated with respiratory symptoms (r=0.430, P=0.042). Meanwhile, the Dice similarity coefficient positively correlated with forced vital capacity % (r=0.577, P=0.004), forced expiratory volume 1% (r=0.526, P=0.012), diffusing capacity of the lungs for carbon monoxide % predicted (r=0.435, P=0.048), 6-minute walk distance (r=0.473, P=0.016), final peripheral oxygen saturation (r=0.534, P=0.004), the extent of fibrosis on chest computed tomography (r=-0.421, P=0.021) and negatively correlated with activity (r=-0.431, P=0.048). CONCLUSION: Lung elasticity decreased in IPF patients and correlated with dyspnea, exercise tolerance, health-related quality of life, lung function, and the extent of pulmonary fibrosis. The lung elasticity based on elastic registration of 3D-PMRI may be a new nonradiation imaging biomarker for quantitative evaluation of the severity of IPF.

Clinical characteristics of hypersensitivity pneumonitis: non-fibrotic and fibrotic subtypes.

BACKGROUND: The presence of fibrosis is a criterion for subtype classification in the newly updated hypersensitivity pneumonitis (HP) guidelines. The present study aimed to summarize differences in clinical characteristics and prognosis of non-fibrotic hypersensitivity pneumonitis (NFHP) and fibrotic hypersensitivity pneumonitis (FHP) and explore factors associated with the presence of fibrosis. METHODS: In this prospective cohort study, patients diagnosed with HP through a multidisciplinary discussion were enrolled. Collected data included demographic and clinical characteristics, laboratory findings, and radiologic and histopathological features. Logistic regression analyses were performed to explore factors related to the presence of fibrosis. RESULTS: A total of 202 patients with HP were enrolled, including 87 (43.1%) NFHP patients and 115 (56.9%) FHP patients. Patients with FHP were older and more frequently presented with dyspnea, crackles, and digital clubbing than patients with NFHP. Serum levels of carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 153, gastrin-releasing peptide precursor, squamous cell carcinoma antigen, and antigen cytokeratin 21-1, and count of bronchoalveolar lavage (BAL) eosinophils were higher in the FHP group than in the NFHP group. BAL lymphocytosis was present in both groups, but less pronounced in the FHP group. Multivariable regression analyses revealed that older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors for the development of FHP. Twelve patients developed adverse outcomes, with a median survival time of 12.5 months, all of whom had FHP. CONCLUSIONS: Older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors associated with the development of FHP. Prognosis of patients with NFHP was better than that of patients with FHP. These results may provide insights into the mechanisms of fibrosis in HP.

External validation of the GAP model in Chinese patients with idiopathic pulmonary fibrosis.

INTRODUCTION: The GAP model was widely used as a simple risk "screening" method for patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: We sought to validate the GAP model in Chinese patients with IPF to evaluate whether it can accurately predict the risk for mortality. METHODS: A total of 212 patients with IPF diagnosed at China-Japan Friendship Hospital from 2015 to 2019 were enrolled. The latest follow-up ended in September 2022. Cumulative mortality of each GAP stage was calculated and compared based on Fine-Gray models for survival, and lung transplantation was treated as a competing risk. The performance of the model was evaluated in terms of both discrimination and calibration. RESULTS: The cumulative mortality in patients with GAP stage III was significantly higher than that in those with GAP stage I or II (Gray's test p < 0.0001). The Harrell c-index for the GAP calculator was 0.736 (95% CI: 0.667-0.864). The discrimination for the GAP staging system were similar with that for the GAP calculator. The GAP model overestimated the mortality rate at 1- and 2-year in patients classified as GAP stage I (6.90% vs. 1.77% for 1-year, 14.20% vs. 6.78% for 2-year). CONCLUSIONS: Our findings indicated that the GAP model overestimated the mortality rate in mild group.

Blood monocyte counts as a prognostic biomarker and predictor in Chinese patients with idiopathic pulmonary fibrosis.

Objectives: We sought to evaluate the prognostic value of blood routine parameters and biochemical parameters, especially inflammation-related biomarkers, and establish an inflammation-related prognostic model in Chinese patients with idiopathic pulmonary fibrosis (IPF). Material/methods: Patients diagnosed as IPF at Beijing Chaoyang Hospital and aged 40 years and older were consecutively enrolled from June 2000 to March 2015, and finally, a total of 377 patients were enrolled in the derivation cohort. The follow-up ended in December 2016. We used Cox proportional hazard model to calculate the hazard ratio (HR) and establish the prognostic model. The discrimination and calibration of the prognostic model were evaluated in an independent validation cohort enrolled from China-Japan Friendship Hospital between January 2015 and December 2019. Results: Multivariate analysis revealed that patients with elevated monocyte-to-red blood cell count ratio (MRR) and monocyte counts showed increased risk of mortality. The clinical-physiological-biomarker (CPB) index and CPB stage we established in this study were a significant predictor, and the C-index for CPB index and CPB stage in the validation cohort was 0.635 (95% CI: 0.558-0.712) and 0.619 (95% CI: 0.544-0.694), respectively. Patients in CPB stage III had the poorest survival. Conclusion: We developed and validated a new inflammation-related prognostic model (CPB index and CPB stage) which was integration of age, gender, FVC (%, predicted), DLCO (%, predicted), Charlson Comorbidity Index, and blood monocyte counts. This prediction model exhibited strong ability in predicting mortality in Chinese patients with IPF.

Idiopathic Pulmonary Fibrosis Registry China study (PORTRAY): protocol for a prospective, multicentre registry study.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterised by a fibrotic histological pattern found in usual interstitial pneumonia. Its causes, pathogenesis, clinical phenotype and molecular mechanisms are poorly defined. Large-scale, multicentre studies are warranted to better understand IPF as a disease in China, its associated risk factors, clinical characteristics, diagnosis, disease progression and treatment. METHODS AND ANALYSIS: The Idiopathic Pulmonary Fibrosis Registry China Study (PORTRAY) is a prospective, multicentre registry study of patients with IPF in China. Eight hundred patients will be enrolled over a 36-month period and followed for at least 3 years to generate a comprehensive database on baseline characteristics and various follow-up parameters including patient-reported outcomes. Biological specimens will also be collected from patients to develop a library of blood, bronchoalveolar lavage fluid and lung biopsy samples, to support future research. As of 15 December 2019, 204 patients from 19 large medical centres with relatively high IPF diagnosis and treatment rates had been enrolled. Patient characteristics will be presented using descriptive statistics. The Kaplan-Meier method will be used for survival analyses. Repeated measures will be used to compare longitudinal changes in lung function, imaging and laboratory tests. Results following analysis have been projected to be available by July 2025. ETHICS AND DISSEMINATION: The study protocol was reviewed and approved by the Institutional Review Board from all the study sites currently recruiting patients. Study results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03666234.

High level production of a Bacillus amlyoliquefaciens chitosanase in Pichia pastoris suitable for chitooligosaccharides preparation.

Chitooligosaccharides (COS) are hydrolytic products of chitosan that are essential in functional food, medicine, and other fields due to their biological activities. Commercial COS are often prepared by the hydrolysis of chitosan by chitosanase. In this study, a glycoside hydrolase family 46 cluster B chitosanase from Bacillus amyloliquefaciens (BaCsn46B) was efficiently expressed in Pichia pastoris. The recombinant enzyme was secreted into the culture medium that reached a total extracellular protein concentration of 4.5 g/L with an activity of 8907.2 U/mL in a high cell density fermenter (5 L). The molecular mass of deglycosylated BaCsn46B was 29.0 kDa. Purified BaCsn46B exhibited excellent enzymatic properties, which had high specific activity (2380.5 U/mg) under optimal reaction conditions (55 °C and pH 6.5). BaCsn46B hydrolyzed chitosan yielded a series of COS with different degrees of polymerization by endo-type cleavage. The end hydrolytic products of BaCsn46B were chitobiose and chitotriose, while no monosaccharide yield was evident in the hydrolytic reaction. The excellent secreted expression level and hydrolytic performance make the enzyme a desirable biocatalyst for the industrial preparation of COS.

IL-25 contributes to lung fibrosis by directly acting on alveolar epithelial cells and fibroblasts.

IMPACT STATEMENT: Our work focused on alveolar epithelial cells (AECs)-derived type-2 cytokine (interleukin [IL]-25) in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We showed that IL-25 and IL-17BR (IL-25's receptor) is upregulated in lung tissues (especially in AECs and lung fibroblasts) of IPF patients and contributes to lung fibrosis by directly activating lung fibroblasts and modulating epithelial-mesenchymal transition (EMT) of AECs. We suggest that IL-25 may be one of the master switches hidden in the milieu of abnormal epithelial-mesenchymal crosstalk. Treatment targeting IL-25 may be the potential and novel method for IPF patients.

Expression and characterization of a novel cold-adapted chitosanase suitable for chitooligosaccharides controllable preparation.

Chitooligosaccharide is widely used as a functional food additive and a valuable pharmacological agent. The transformation of chitinous biomass into valuable bioactive chitooligosaccharides is one of the most exciting applications of chitosanase. A novel glycoside hydrolase (GH) family 46 chitosanase (GsCsn46A) from rhizobacterium Gynuella sunshinyii was cloned and heterologously expressed in Escherichia coli. GsCsn46A showed maximal activity at pH 5.5 and 30 °C. GsCsn46A featured remarkable cold-adapted property, which controllably hydrolyzed chitosan to three types of chitooligosaccharides at the mild reaction condition (reaction condition: pH 5.5 at 30 °C; method for stopping the reaction: 50 °C for 30 min). The yields of three types of chitooligosaccharides products (degree of polymerization (DP): 2-7, 2-5 and 2-3) were 70.9%, 87.1% and 94.6% respectively. This novel cold-adapted chitosanase provides a cleaner production process for the controllable preparation of chitooligosaccharides with the specific DP.

Effect of HA330 resin-directed hemoadsorption on a porcine acute respiratory distress syndrome model.

BACKGROUND: Blood purification is an emerging approach to dampening the cytokine storm. This study aims to assess the efficacy of HA330 resin-directed hemoadsorption (HA) on endotoxin-induced porcine acute respiratory distress syndrome (ARDS) model. METHODS: Twenty-four Chinese domestic pigs were allocated into saline group receiving intravenous infusion of saline (N = 6) and endotoxin group receiving intravenous infusion of LPS (N = 18). When ALI model was initially diagnosed, six pigs in the LPS and saline group were killed for BALF and histopathological analysis. The remaining 12 pigs in LPS group received 3-h HA (N = 6) or HA-sham (N = 6) treatment, respectively. Following another 5-h observation, animals were killed. Variables on hemodynamics, blood gases and lung mechanics were recorded at a series of time points. Differentially expressed cytokines and proteins were determined by ELISA and proteomics. RESULTS: HA treatment significantly improved injured oxygenation induced by LPS. HA also partially improved the barrier permeability and reduced lung edema and inflammation/injury induced by LPS infusion. Proteomic analysis showed the differentially expressed proteins between HA- and HA-sham-treated groups mostly belonged to the categories of acute inflammation/immune response, and proteolysis. CONCLUSIONS: Hemoadsorption improved ARDS possibly by blunting the cytokine storm and by restoring homeostasis of the disordered proteome milieu in the exudative phase.

Phosgene- and chlorine-induced acute lung injury in rats: comparison of cardiopulmonary function and biomarkers in exhaled breath.

This study compares changes in cardiopulmonary function, selected endpoints in exhaled breath, blood, and bronchoalveolar lavage fluid (BAL) following a single, high-level 30-min nose-only exposure of rats to chlorine and phosgene gas. The time-course of lung injury was systematically examined up to 1-day post-exposure with the objective to identify early diagnostic biomarkers suitable to guide countermeasures to accidental exposures. Chlorine, due to its water solubility, penetrates the lung concentration-dependently whereas the poorly water-soluble phosgene reaches the alveolar region without any appreciable extent of airway injury. Cardiopulmonary endpoints were continually recorded by telemetry and barometric plethysmography for 20h. At several time points blood was collected to evaluate evidence of hemoconcentration, changes in hemostasis, and osteopontin. One day post-exposure, protein, osteopontin, and cytodifferentials were determined in BAL. Nitric oxide (eNO) and eCO2 were non-invasively examined in exhaled breath 5 and 24h post-exposure. Chlorine-exposed rats elaborated a reflexively-induced decreased respiratory rate and bradycardia whereas phosgene-exposed rats developed minimal changes in lung function but a similar magnitude of bradycardia. Despite similar initial changes in cardiac function, the phosgene-exposed rats showed different time-course changes of hemoconcentration and lung weights as compared to chlorine-exposed rats. eNO/eCO2 ratios were most affected in chlorine-exposed rats in the absence of any marked time-related changes. This outcome appears to demonstrate that nociceptive reflexes with changes in cardiopulmonary function resemble typical patterns of mixed airway-alveolar irritation in chlorine-exposed rats and alveolar irritation in phosgene-exposed rats. The degree and time-course of pulmonary injury was reflected best by eNO/eCO2 ratios, hemoconcentration, and protein in BAL. Increased fibrin in blood occurred only in chlorine-exposed rats 1-day post-exposure. Hence, the analysis of NO and CO2 in exhaled breath, including endpoints in blood mirroring changes in the peripheral to pulmonary fluid distribution, seem to be sensitive diagnostic endpoints readily available for early prognostic assessment of severity of injury and efficacy of any chosen countermeasure.

Corticosteroids found ineffective for phosgene-induced acute lung injury in rats.

Various therapeutic regimes have been proposed with limited success for treatment of phosgene-induced acute lung injury (P-ALI). Corticoids were shown to be efficacious against chlorine-induced lung injury but there is still controversy whether this applies also to P-ALI. This study investigates whether different regimen of curatively administered budesonide (BUD, 10 mg/kg bw, i.p. bid; 100 mg/m(3)×30 min, nose-only inhalation), mometasone (MOM, 3 mg/kg bw, i.p. bid) and dexamethasone (DEX, 10, 30 mg/kg bw, i.p. bid), show efficacy to alleviate P-ALI. Efficacy of drugs was judged by nitric oxide (eNO) and carbon dioxide (eCO2) in exhaled air and whether these non-invasive biomarkers are suitable to assess the degree of airway injury (chlorine) relative to alveolar injury (phosgene). P-ALI related analyses included lung function (enhanced pause, Penh), morbidity, increased lung weights, and protein in bronchial alveolar lavage fluid (BALF) one day postexposure. One of the pathophysiological hallmarks of P-ALI was indicated by increased Penh lasting for approximately 20 h postexposure. Following the administration of BUD, this increase could be suppressed; however, without significant improvement in survival and lung edema (increased lung weights and BALF-protein). Collectively, protocols shown to be efficacious for chlorine (Chen et al., 2013) were ineffective and even increased adversity in the P-ALI model. This outcome warrants further study to seek for early biomarkers suitable to differentiate chlorine- and phosgene-induced acute lung injury at yet asymptomatic stage. The patterns of eNO and eCO2 observed following exposure to chlorine and phosgene may be suitable to guide the specialized clinical interventions required for each type of ALI.