SACE and IL-2R as serum biomarkers for evaluation of multi-organ involvement and prognosis of sarcoidosis.

BACKGROUND: Serum biomarkers in the evaluation of organ involvement and prognostic monitoring of sarcoidosis have not been determined. The purpose of this study was to identify common biomarkers that could be used to assess organ involvement and monitor outcomes in sarcoidosis patients. METHODS: From Mar 2013 to Sep 2021, patients with newly diagnosed pulmonary sarcoidosis were enrolled in this study in Shanghai Pulmonary Hospital. The information from medical records was retrospectively collected including diagnosis, organ involvement, laboratory tests and follow up data. Differences of continuous variables between groups were analyzed by unpaired Student's t-test. Multivariate logistic regression model was performed to identify potential independent factors associated with multiple organ involvement. RESULTS: A total of 832 patients were included in the study. There were 339 (40.7%) patients with single organ pulmonary involvement, while 493 (59.3%) patients had two to seven organs involved. Among the routine serum tests, only the serum angiotensin converting enzyme (SACE) level was an independent factor of multiple organ involvement. Compared to those patients without involvement, SACE levels were higher in patients with extra-thoracic lymph node, skin, or spleen involvement as well as abnormal calcium metabolism. Interleukin-2 receptor (IL-2R) levels were higher in patients with extra-thoracic lymph node, spleen involvement and abnormal calcium metabolism than in those without it. The mean levels of SACE and IL-2R showed upward trends paralleling the increase on number of organs involved. In follow up, SACE and IL-2R levels were both decreased in an improved patient group, while there was no obvious difference was noticed before and after treatment in patients with persistent disease. CONCLUSION: SACE and IL-2R were useful as serum biomarkers in the initial evaluation of organ involvement as well as monitoring prognosis in sarcoidosis.

The diagnostic value of transbronchial lung cryobiopsy combined with rapid on-site evaluation in diffuse lung diseases: a prospective and self-controlled study.

BACKGROUND: The etiology of interstitial lung diseases (ILDs) is varied. Early diagnosis and a specific pathological type could significantly improve the prognosis. Mostly, it is difficult to make the etiology diagnosis of ILD through traditional biopsy methods. It will be of great significance to explore an effective biopsy method. METHODS: The prospective study was designed to evaluate the diagnostic value of transbronchial lung cryobiopsy (TBCB) combined with rapid on-site evaluation (ROSE), compared with conventional transbronchial lung biopsy (TBLB), in a large sample of ILD patients. All patients enrolled will undergo both TBLB and TBCB procedures. The study will observe the differences in the diagnostic efficiency of pathological typing and incidence of operation-related complications between TBCB and TBLB. Besides, it will analyze the relationship between the time of biopsy and the incidence of complications, the relationship between freezing time, size of specimen, and complications. And it will evaluate the consistency of pathological, clinical, and radiology. DISCUSSION: It may be the first time that ROSE technique will be used in the diagnosis of ILD. The results of this study will clarify the value of TBCB in the diagnosis of ILD and confirm its safety and effectiveness, which is expected to significantly improve the efficiency of diagnosis in ILD patients. TRAIL REGISTRATION: The trial was registered on the Chinese Clinical Trial Registry website ( http://www.chictr.org.cn/showproj.aspx?proj=57834 ) (Registration number: ChiCTR2000035492).

The effects of antifungal therapy on the recurrence of aspergillus infection after pulmonary aspergilloma resection: a study protocol for a single-center, prospective, non-blind, randomized, 24-month, parallel group study.

BACKGROUND: In recent years, the incidence of pulmonary aspergilloma has increased. The harm of aspergilloma is life-threatening massive hemoptysis, and the conventional treatment is surgical treatment. However, whether the antifungal treatment after surgery is required and the course of treatment before and after surgery are still unclear. METHODS: In this study, patients with pulmonary aspergilloma confirmed pathologically after surgery will be selected as subjects to conduct a single-center, randomized, parallel grouping, prospective, 2-year clinical study. Through regular visits, the recurrence of aspergillus infection, quality of life, lung function indicators, safety of antifungal therapy and other indicators were recorded to evaluate the recurrence risk of aspergillus infection and safety of antifungal agents. Cox proportional risk regression model was used to analyze the influencing factors of antifungal therapy on aspergillus infection recurrence after aspergillus bulbectomy. Cox multiple regression model was used for optimal model fitting, and regression coefficient (ß), relative risk (RR) and 95% confidence interval of RR were calculated. DISCUSSION: The study will explore whether antifungal therapy could improve the quality of life, reduce the recurrence of aspergillus infection, and ultimately improve the prognosis of patients with aspergilloma. The study results will provide high-quality evidence-based medical evidence for the formulation, revision and optimization of international and domestic clinical guidelines and expert consensus on chronic aspergillus lung disease, effectively improve the clinical treatment effect of aspergilloma, and form the latest concept of diagnosis and treatment of aspergilloma. TRIAL REGISTRATION: The trial was registered on the Chinese Clinical Trial Registry website ( https://www.chictr.org.cn/showprojen.aspx?proj=33231 ). Registration number: ChiCTR1800019990.

The Role of Infection in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

BACKGROUND: Acute exacerbation of IPF (AE-IPF) is associated with high mortality. We studied changes in pathogen involvement during AE-IPF and explored a possible role of infection in AE-IPF. OBJECTIVES: Our purpose is to investigate the role of infection in AE-IPF. METHODS: Overall, we recruited 170 IPF patients (48 AE-IPF, 122 stable) and 70 controls at Shanghai Pulmonary Hospital. Specific IgM against microbial pathogens and pathogens in sputum were assessed. RNA sequences of pathogens in nasopharyngeal swab of IPF patients were detected by PathChip. A panel of serum parameters reflecting immune function were assessed. RESULTS: Antiviral/bacterial IgM was higher in IPF vs. controls and in AE-IPF vs. stable IPF. Thirty-eight different bacterial strains were detected in IPF patient sputum. Bacteria-positive results were found in 9/48 (18.8%) of AE-IPF and in 26/122 (21.3%) stable IPF. Fifty-seven different viruses were detected in nasopharyngeal swabs of IPF patients. Virus-positive nasopharyngeal swabs were found in 18/30 (60%) of tested AE-IPF and in 13/30 (43.3%) of stable IPF. AE-IPF showed increased inflammatory cytokines (IL-6, IFN-γ, MIG, IL-17, and IL-9) vs. stable IPF and controls. Mortality of AE-IPF in one year (39.5%) was higher compared to stable IPF (28.7%).Conclusions. IPF patients had different colonization with pathogens in sputum and nasopharyngeal swabs; they also displayed abnormally activated immune response, which was exacerbated during AE-IPF.

Preliminary characterizations of a serum biomarker for sarcoidosis by comparative proteomic approach with tandem-mass spectrometry in ethnic Han Chinese patients.

BACKGROUND: The diagnosis of sarcoidosis is still a significant challenge in China because of the need to exclude other diseases including granulomatous infections and malignancies that may be clinically and radiographically similar. The specific aim of the study is to search for serum protein biomarkers of sarcoidosis and to validate their clinical usefulness in differential diagnosis. METHODS: Serum samples were collected from patients with sarcoidosis (n = 37), and compared to those from patients with tuberculosis (n = 20), other pulmonary diseases (n = 20), and healthy volunteers (n = 20) for determination of sarcoidosis-specific or -associated protein expression profiles. The first part of this study focused on proteomic analysis of serum from patients with sarcoidosis to identify a pattern of peptides capable of differentiating the studied populations using the ClinProt profiling technology based on mass spectrometry. Enzyme Linked Immunosorbent Assay (ELISA) was then used to verify corresponding elevation of the serum protein concentration of the potential biomarkers in the same patients sets. Receiver operating characteristic curve (ROC) analyses was performed to determine the optimal cutoff value for diagnosis. Immunohistochemistry was carried out to further confirm the protein expression patterns of the biomarkers in lung tissue. RESULTS: An unique protein peak of M/Z 3,210 Daltons (Da) was found to be differentially expressed between the sarcoidosis and control groups and was identified as the N-terminal peptide of 29 amino acids (94-122) of serum amyloid A (SAA). ELISA confirmed that the serum SAA level was significantly higher in the sarcoidosis group than that of the other 3 control groups (p < 0.05). The cutoff for serum SAA concentration determined by ROC analysis was 101.98 ng/ml, with the sensitivity and specificity of 96.3% and 52.5%, respectively. Immunohistochemical staining showed that the SAA depositions in lung tissue of the sarcoidosis patients were also significantly more intense than in non-sarcoid lung tissue (p < 0.05). CONCLUSION: This is the first study to investigate serum protein markers in Chinese subjects with sarcoidosis. This study shows that the serum SAA expression profiles were different between the sarcoidosis and non-sarcoidosis groups. SAA may be a potential serum biomarker for ruling-out the diagnosis of sarcoidosis in Chinese subjects.

Factors associated with rapid progression in fibrotic interstitial lung disease.

Background: Early identification of fibrotic interstitial lung disease (F-ILD) patients with high risk of progression will help initiate early therapeutic intervention and potential improvement of outcomes. This study was designed to assess the predictors of progression in patients with F-ILD. Methods: Patients with F-ILD in Shanghai Pulmonary Hospital between January 1, 2019 and July 31, 2021 were retrospectively analyzed. The patients enrolled were divided into progressive group and non-progressive group according to the specified criteria. Baseline characteristics were collected and a multivariate regression was conducted to identify independent predictors of progression. Results: Of the 177 F-ILD cases, 87 were enrolled in the progressive group and 90 were in the non-progressive group. The cohort included 11 types of F-ILD, primarily were connective tissue disease-associated interstitial lung disease (CTD-ILD) (43, 24.3 %), idiopathic pulmonary fibrosis (IPF) (39, 22.0 %), interstitial pneumonia with autoimmune features (IPAF) (32, 18.1 %), and unclassifiable (23, 13.0 %). The highest proportion of progression was seen in nonspecific interstitial pneumonia (NSIP) subgroup (66.7 %), followed by IPF (59.0 %) and HP (57.1 %). After adjusting for gender and age, a course of disease longer than 9.5 months (OR: 2.633; 95 % CI: 1.190-5.826, P = 0.017), lymphocyte in peripheral blood more than 2.24 (109/L) (OR: 2.670; 95 % CI: 1.095-6.510, P = 0.031), and emphysema in high-resolution computed tomography (HRCT) (OR: 2.387; 95 % CI: 1.017-5.640, P = 0.046) were independent predictors of progression in F-ILD patients. Conclusions: This study suggested that in patients with F-ILD, long course of disease, elevated blood lymphocyte and emphysema on HRCT were independent predictors of progression, which may suggest utility in early therapeutic intervention.

Levalbuterol vs. albuterol for hospitalized patients with COPD in China: cost-utility and budget impact analysis.

OBJECTIVES: For hospitalized patients with chronic obstructive pulmonary disease (COPD), albuterol and levalbuterol can both be used as relievers to alleviate bronchoconstriction. This study aimed to evaluate levalbuterol and albuterol's cost-utility and budget impact in hospitalized patients with COPD. INTERVENTIONS: A cost-utility analysis was used to evaluate the impact on the costs of nebulized levalbuterol verse albuterol in hospitalized patients with COPD. The decision tree model was employed to estimate the incremental cost per quality-adjusted life year in the admission setting. A budget impact model was used to examine the impact of budget on levalbuterol's entry into the Chinese market from the healthcare system's perspective. One-way sensitivity and probabilistic sensitivity analyses were performed to test the uncertainty of the parameters. RESULTS: The cost-utility results showed that levalbuterol saved ¥495.7 ($105.1) per hospitalization, while the budget impact analysis revealed a potential saving of ¥22.3 ($6.8) million in 3 years. The sensitivity analysis indicated that the results were robust to the changes in input parameter values. CONCLUSION: Levalbuterol is a cost-saving option for treating hospitalized patients with COPD in China.

Chronic obstructive pulmonary disease (COPD) is a common disease in China, with an increased financial burden over the years. Nebulized albuterol is the most commonly used short-acting beta2-agonist, often regarded as the initial bronchodilator to treat hospitalized COPD patients. Its R-isomer, levalbuterol, entered the Chinese market in 2019. The new intervention always impacts the expenditure of the health system. We built a cost-utility and budget impact model to analyze the difference between albuterol and levalbuterol. The cost-utility results showed that levalbuterol saved ¥495.7 ($105.1) per hospitalization compared with albuterol, while the budget impact analysis revealed a potential saving of ¥22.3 ($6.8) million in 3 years.

Value of 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the differential diagnosis of sarcoidosis and lung cancer with lymph node metastasis: a retrospective study.

Background: Fluorine 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been proven to be valuable in guiding the diagnosis and management of sarcoidosis. However, its differential value for sarcoidosis is unclear. The objective of this study was to explore the value of 18F-FDG PET/CT in differentiation sarcoidosis from lung cancer with lymph node metastasis. Methods: A total of 361 consecutively diagnosed sarcoidosis patients and 1,944 consecutively diagnosed lung cancer patients at Shanghai Pulmonary Hospital were retrospectively reviewed. Among them, 85 patients diagnosed with sarcoidosis and 94 lung cancer patients with lymph node metastasis were enrolled. Demographic data and 18F-FDG PET/CT parameters were analyzed by the chi-square test or independent sample Student's t-test. Receiver operating characteristic (ROC) curves were generated to identify cut-off values. Multivariate logistic regression was performed to identify independent predictors of sarcoidosis on 18F-FDG PET/CT, and those with P<0.1 were included in a regression model using the forward log rank (LR) method to generate a ROC curve. Results: The ratio of extrapulmonary lymph node involvement in sarcoidosis patients was significantly higher than that in lung cancer patients (64.7% vs. 29.8%, P<0.001). After adjusting for gender and age, extrapulmonary lymph node involvement [odds ratio (OR): 3.160; 95% confidence interval (CI): 1.105-9.035], maximum standardized uptake value (SUVmax) of mediastinum/hilar lymph nodes >13.86 (OR: 3.245; 95% CI: 1.045-10.083), and short axis of the corresponding lymph node >11.5 mm (OR: 5.470; 95% CI: 1.149-26.037) on 18F-FDG PET/CT were independent predictors of sarcoidosis, with a sensitivity and specificity of 77.5% and 69.3%, respectively. The area under the curve was 0.769. Conclusions: 18F-FDG PET/CT could be helpful to distinguish sarcoidosis from lung cancer patients with lymph node metastasis.

Idiopathic Pulmonary Fibrosis Mortality Risk Prediction Based on Artificial Intelligence: The CTPF Model.

Background: Idiopathic pulmonary fibrosis (IPF) needs a precise prediction method for its prognosis. This study took advantage of artificial intelligence (AI) deep learning to develop a new mortality risk prediction model for IPF patients. Methods: We established an artificial intelligence honeycomb segmentation system that segmented the honeycomb tissue area automatically from 102 manually labeled (by radiologists) cases of IPF patients' CT images. The percentage of honeycomb in the lung was calculated as the CT fibrosis score (CTS). The severity of the patients was evaluated by pulmonary function and physiological feature (PF) parameters (including FVC%pred, DLco%pred, SpO2%, age, and gender). Another 206 IPF cases were randomly divided into a training set (n = 165) and a verification set (n = 41) to calculate the fibrosis percentage in each case by the AI system mentioned previously. Then, using a competing risk (Fine-Gray) proportional hazards model, a risk score model was created according to the training set's patient data and used the validation data set to validate this model. Result: The final risk prediction model (CTPF) was established, and it included the CT stages and the PF (pulmonary function and physiological features) grades. The CT stages were defined into three stages: stage I (CTS≤5), stage II (5 < CTS<25), and stage III (≥25). The PF grades were classified into mild (a, 0-3 points), moderate (b, 4-6 points), and severe (c, 7-10 points). The AUC index and Briers scores at 1, 2, and 3 years in the training set were as follows: 74.3 [63.2,85.4], 8.6 [2.4,14.8]; 78 [70.2,85.9], 16.0 [10.1,22.0]; and 72.8 [58.3,87.3], 18.2 [11.9,24.6]. The results of the validation sets were similar and suggested that high-risk patients had significantly higher mortality rates. Conclusion: This CTPF model with AI technology can predict mortality risk in IPF precisely.

Establishment and validation of a predictive model for nontuberculous mycobacterial infections in acid-fast bacilli smear-positive patients.

INTRODUCTION: Nontuberculous mycobacteria (NTM) and pulmonary tuberculosis (PTB) are difficult to distinguish in initial acid-fast bacilli (AFB) smear-positive patients. OBJECTIVES: Establish a predictive model to identify more effectively NTM infections in initial AFB patients. METHODS: Consecutive AFB smear-positive patients in the Respiratory Department of Shanghai Pulmonary Hospital from January 2019 to February 2020 were retrospectively analysed. A multivariate regression was used to determine the independent risk factors for NTM. A receiver operating characteristic (ROC) curve was used to determine the model's predictive discrimination. The model was validated internally by a calibration curve and externally for consecutive AFB smear-positive patients from March to June 2020 in this institution. RESULTS: Presenting with haemoptysis, bronchiectasis, a negative QuantiFERON tuberculosis (QFT) test and being female were characteristics significantly more common in patients with NTM (P ≤ 0.001), when compared with PTB. The involvement of right middle lobe, left lingual lobe and cystic change was more commonly seen on chest high-resolution computed tomography (HRCT) in patients with NTM (P < 0.05), compared with PTB. Multivariate regression showed female, bronchiectasis, negative test for QFT and right middle lobe lesion were independent risk factors for NTM (P < 0.05). A ROC curve showed a sensitivity and specificity of 85.9% and 93.4%, respectively, and the area under the curve (AUC) was 0.963. Moreover, internal and external validation both confirmed the effectiveness of the model. CONCLUSIONS: The predictive model would be useful for early differential diagnosis of NTM in initial AFB smear-positive patients.

Predictors of Mortality in Progressive Fibrosing Interstitial Lung Diseases.

Background: Progressive fibrosing interstitial lung disease (PF-ILD) and idiopathic pulmonary fibrosis (IPF) share similar progression phenotype but with different pathophysiological mechanism. The purpose of this study was to assess clinical characteristics and outcomes of patients with PF-ILD in a single-center cohort. Methods: Patients with PF-ILD treated in Shanghai Pulmonary Hospital from Jan. 2013 to Dec. 2014 were retrospectively analyzed. Baseline characteristics and clinical outcomes were collected for survival analysis to identifying clinical predictors of mortality. Results: Among 608 patients with ILD, 132 patients met the diagnostic criteria for PF-ILD. In this single-center cohort, there were 51 (38.6%) cases with connective tissue disease-associated interstitial lung disease (CTD-ILD) and 45 (34.1%) with unclassifiable ILDs. During follow-up, 83 patients (62.9%) either died (N = 79, 59.8%) or underwent lung transplantations (N = 4, 3.0%) with a median duration follow-up time of 53.7 months. Kaplan-Meier survival curves revealed that the 1, 3 and 5-years survival of PF-ILD were 90.9, 58.8 and 48.1%, respectively. In addition, the prognosis of patients with PF-ILD was similar to those with IPF, while it was worse than non-PF-ILD ones. Multivariate Cox regression analysis demonstrated that high-resolution computed tomography (HRCT) scores (HR 1.684, 95% CI 1.017-2.788, p = 0.043) and systolic pulmonary artery pressure (SPAP) > 36.5 mmHg (HR 3.619, 95%CI 1.170-11.194, p = 0.026) were independent risk factors for the mortality of PF-ILD. Conclusion: Extent of fibrotic changes on HRCT and pulmonary hypertension were predictors of mortality in patients with PF-ILD.

Comparison of traditional methods and high-throughput genetic sequencing in the detection of pathogens in pulmonary infectious diseases.

BACKGROUND: The major causes of pulmonary infections are various microorganisms. This study aimed to compare the positive rates of pathogenic microorganism DNA/RNA high-throughput genetic sequencing (PMseq), which is an emerging technique, with traditional methods for pulmonary disease detection, and to investigate the differences in different sample types. METHODS: Bronchoalveolar lavage fluid (BALF) and venous blood samples from 104 patients were collected for detection. RESULTS: The positive rates of PMseq in BALF and venous blood were both significantly higher than those of traditional methods in the same sample (P<0.001). For BALF, the detection sensitivities were 96.9% for non-febrile patients and 100% for febrile patients. For venous blood, the detection sensitivities were 50.0% for non-febrile patients and 81.3% for febrile patients. There was no statistical difference in the sensitivity of venous blood samples with or without fever (P=0.075). For patients without fever, the sensitivity of BALF was much higher than venous blood samples (P<0.001). In patients with fever, there were no significant differences between different samples. CONCLUSIONS: This study showed that PMseq has a higher positive rate for the detection of pulmonary diseases. For patients without fever, it is recommended to use BALF instead of venous blood samples because of the higher sensitivity. However, for patients with fever, venous blood samples can be used when bronchoalveolar lavage is inconvenient.

Toll-like receptors 2 expression in mediastinal lymph node of patients with sarcoidosis.

BACKGROUND: Toll-like receptors (TLRs) play a vital role as a first defense mechanism linking the innate with the adaptive immune system. Prior studies showed that TLR2 participated in immune responses of sarcoidosis. However, the role of TLR2 in the progression of mediastinal lymph nodes associated with sarcoidosis is still unknown. The current study aims to investigate the expression of Toll-like receptors 2 (TLR2) in mediastinal lymph nodes of patients with sarcoidosis. METHODS: Mediastinal lymph nodes biopsy specimens were collected from 10 patients with sarcoidosis and 11 normal controls. The expression of TLR2 in mediastinal lymph nodes was detected by immunohistochemistry. RESULTS: In mediastinal lymph nodes specimens, immunohistochemical examination revealed that expression of TLR2 could be detected in sarcoidosis patients, while it was scarcely detected in the mediastinal lymph nodes of control. The mean optical density of TLR2 in mediastinal lymph nodes of sarcoidosis was significantly higher than controls (124.9±24.3 vs. 92.6±35.2, P=0.026). Among patients with sarcoidosis, correlation analysis showed that the mean optical density of TLR2 in mediastinal lymph nodes positively correlated with the level of 24-hour urinary calcium (R=0.781, P=0.038). CONCLUSIONS: The expression of TLR2 was upregulated in mediastinal lymph nodes of sarcoidosis patients. The expression of TLR2 in mediastinal lymph nodes was associated with the level of 24-hour urinary calcium, suggesting that TLR2 might become another predictor of disease activity.

Azithromycin treats diffuse panbronchiolitis by targeting T cells via inhibition of mTOR pathway.

Azithromycin (AZM), that is a macrolide antibiotic, has been found to treat diffuse panbronchiolitis (DPB) effectively. However, the mechanism of action underlying the therapeutic effects remains unclear. We selected 64 patients with DPB from 305 patients who were diagnosed with DPB at the outpatient clinic in Shanghai Pulmonary Hospital from Jan 2010 to Oct 2014. The primary PBLs, CD4 + T cells, and Jurkat T cells were treated with AZM or erythromycin (EM), and the effects of AZM and EM on IL-17A and CXCL-2 production, proliferation, apoptosis and autophagy were evaluated. AZM and EM significantly inhibited IL-17A and CXCL-2 production in patients' PBLs (all P < 0.05). AZM significantly inhibited proliferation and promoted apoptosis of T cells from DPB patients. AZM can enhance autophagosome formation of T cells by suppressing S6RP phosphorylation, which is a downstream target of mTOR pathway (all P < 0.05). AZM and EM significantly decreased secreted IL-17A levels (P < 0.05) in the primary CD4 + T cells of patients with DPB. AZM may treat DPB patients by targeting cytokine production, proliferation, apoptosis and autophagy of T cell. The mechanism of therapeutic effects of AZM on DPB may be associated with a specific inhibition of mTOR pathway in the T lymphocytes.