The clinical association of programmed death-1/PD-L1 axis, myeloid derived suppressor cells subsets and regulatory T cells in peripheral blood of stable COPD patients.

Background: Myeloid-derived suppressor cells (MDSCs) have crucial immunosuppressive role in T cell dysfunction in various disease processes. However, the role of MDSCs and their impact on Tregs in COPD have not been fully understood. The aim of the present study is to investigate the immunomodulatory role of MDSCs and their potential impact on the expansion and function of Tregs in COPD patients. Methods: Peripheral blood samples were collected to analyze circulating MDSCs, Tregs, PD-1/PD-L1 expression to assess the immunomodulatory role of MDSC and their potential impact on the expansion and function of Treg in COPD. A total of 54 COPD patients and 24 healthy individuals were enrolled in our study. Flow cytometric analyses were performed to identify granulocytic MDSCs (G-MDSCs), monocytic MDSCs (M-MDSCs), Tregs, and the expression of PD-1/PD-L1(L2) on MDSCs and Tregs in peripheral blood. Results: Our results revealed a significantly higher percentage of G-MDSCs and M-MDSCs (p < 0.001) in COPD patients compared to the healthy controls. Additionally, a significantly higher proportion of peripheral blood Tregs was observed in COPD patients. Furthermore, an increased expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on Tregs (p < 0.01) was detected in COPD patients. The expression of PD-1 on CD4+ Tcells and Tregs, but not CD8+Tcells, was found to be increased in patients with COPD compared to controls. Furthermore, an elevated expression of PD-L1 on M-MDSCs (p < 0.01) was also observed in COPD patients. A positive correlation was observed between the accumulation of M-MDSCs and Tregs in COPD patients. Additionally, the percentage of circulating M-MDSCs is positively associated with the level of PD-1 (r = 0.51, p < 0.0001) and CTLA-4 (r = 0.42, p = 0.0014) on Tregs in COPD. Conclusion: The recruitment of MDSCs, accumulation of Tregs, and up-regulation of CTLA-4 on Treg in COPD, accompanied by an increased level of PD-1/PD-L1, suggest PD-1/PD-L1 axis may be potentially involved in MDSCs-induced the expansion and activation of Treg at least partially in COPD.

Myeloid­derived suppressor cell accumulation induces Treg expansion and modulates lung malignancy progression.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T cell immunity in tumor-bearing hosts. The present study aimed to examine roles of T and MDSC subsets in lung malignancy. The study analyzed 102 cases with lung malignancy and 34 healthy individuals. Flow cytometry was performed for identification of T cell and MDSC subsets and their phenotypic characteristics in peripheral blood. The lung malignancy cases exhibited lower frequencies of granulocyte-like MDSCs (G-MDSCs) expressing PD-L2 and PD-L1 than healthy controls (P=0.013 and P<0.001, respectively). Additionally, there was a higher frequency of monocyte-like MDSCs (M-MDSCs) expressing PD-L1 in the peripheral blood of patients with lung malignancy than healthy controls (P<0.001). The frequencies of G-MDSCs and M-MDSCs were positively correlated with proportions of PD-1+ and CTLA-4+ regulatory T cells (Tregs). In vitro co-culture assay demonstrated M-MDSCs of lung malignancy enhanced naive T cell apoptosis and promoted Treg subset differentiation compared with M-MDSCs of healthy controls. The findings suggested accumulation of MDSC subsets in lung malignancy and MDSCs expressing PD-L2 and PD-L1 induced Treg expansion by binding to PD-1 on the surface of Tregs.

Pulmonary histoplasmosis on the Chinese mainland: two case reports and literature review.

INTRODUCTION: Pulmonary histoplasmosis is a fungal disease that is endemic in North and Central America. It is relatively rare in China and commonly misdiagnosed as tuberculosis or cancer due to nonspecific clinical and radiographic manifestations. Rapid and accurate pathogen tests are critical for the diagnosis of pulmonary histoplasmosis. METHODOLOGY: We report two cases of pulmonary histoplasmosis. We collected all the relevant case reports on the Chinese mainland (from 1990 to 2022) to analyze features of this disease among Chinese patients. RESULTS: A total of 42 articles reporting 101 cases were identified, and the two cases reported in this article were also included for analysis. Sixty-three (61.2%) patients had respiratory symptoms and 35 (34.0%) patients were asymptomatic. The most common radiographic findings were pulmonary nodules or masses (81.6%). Twenty-two (21.4%) patients were misdiagnosed as tuberculosis, and 37 (35.9%) were misdiagnosed as lung tumors before pathological findings. Metagenomic next­generation sequencing (mNGS) testing provided a rapid diagnostic and therapeutic basis for three patients. CONCLUSIONS: Clinical features and imaging findings of pulmonary histoplasmosis are not specific. Relevant epidemiological history and timely pathogen detection are important for diagnosis. mNGS can shorten the time required for diagnosis and allow earlier initiation of targeted antibiotic therapy.

First case report of a novel KIF13A-ALK fusion in a lung adenocarcinoma patient and response to alectinib with a 4-year follow-up.

The prevalence of Anaplastic Lymphoma Kinase gene (ALK) fusion is about 5% among patients with lung adenocarcinoma, underscoring the importance of pinpointing distinct fusion variants for optimizing treatment approaches. This is the first reported case of a 74-year-old female with stage IV lung adenocarcinoma, featuring a novel Kinesin Family Member 13A (KIF13A)-ALK fusion, identified via next-generation sequencing (NGS) and confirmed with fluorescence in situ hybridization (FISH). Initially undergoing chemotherapy and then crizotinib, she achieved a partial response (PR) before progressing with multiple bone metastases. However, subsequent treatment with alectinib as a third-line option yielded positive results. A stable disease state persisted for an impressive 31 months of progression-free survival (PFS), accompanied by minimal toxicity symptoms. Up until now, a remarkable near 4-year span of overall survival (OS) has been consistently observed and monitored. This report of a KIF13A-ALK fusion case benefit significantly from alectinib with extensive follow-up. The case diversifies the array of ALK fusion partners and holds clinical relevance in refining therapeutic choices for KIF13A-ALK fusion-associated lung cancer.

The distribution of myeloid-derived suppressor cells subsets and up-regulation of programmed death-1/PD-L1 axis in peripheral blood of adult CAP patients.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) have been reported to expand and have a potent ability in the expansion of regulatory T cells in malignant and infectious disease. The current study was performed to investigate the role of MDSCs and possible immune mechanisms in dampening immune responses of community acquired pneumonia (CAP). METHODS: This was a single-center cross-sectional study. The distribution of MDSCs subsets, the PD-1/PD-L1(L2) level of MDSCs subsets and Tregs in the peripheral blood of adult CAP patients and healthy control were measured by flow cytometry analysis. RESULTS: Peripheral blood mononuclear cells (PBMCs) from 63 adult CAP patients contained an elevated frequency of both G-MDSC (4.92±0.30 vs 2.25±0.21,p<0.0001) and M-MDSC (19.40±1.30 vs 9.64±0.57,p<0.001) compared to healthy controls. Treg in the peripheral blood of CAP patients exhibited increased expression of PD-1 and CTLA-4, accompanied by no difference of their frequency. Moreover, up-regulated expression of PD-L1 on MDSC subsets in the peripheral blood of CAP patients was also revealed. Of note, the frequency of circulating MDSCs subset displayed a positive correlation with neutrophil count percentage in blood in CAP patients. CONCLUSIONS: In summary, the significant expansion of circulating MDSCs subsets and the up-regulated expression of PD-1/PD-L1 level in CAP patients may suggest the possible involvement of PD-1/PD-L1axis in MDSCs mediated immune regulation on Treg at least partially in CAP patients.

Random forest model can predict the prognosis of hospital-acquired Klebsiella pneumoniae infection as well as traditional logistic regression model.

OBJECTIVE: To explore if random forest (RF) model can predict the prognosis of hospital-acquired Klebsiella pneumoniae infection as well as traditional logistic regression(LR) model. METHODS: A total of 254 cases of hospital-acquired Klebsiella pneumoniae infection in a tertiary hospital in Beijing from January 2016 to December 2020 were retrospectively collected. Appropriate influencing factors were selected by referring to relevant articles from the aspects of basic clinical information and contact history before infection, and divided into a training set and a test set. Both the RF and LR models were trained by the training set, and using testing set to compare these two models. RESULTS: The prediction accuracy of the LR model was 87.0%, the true positive rate of the LR model was 94.7%; the false negative rate of the LR model was 5.3%; the false positive rate of the LR model was 35%; the true negative rate of the LR model was 65%; the sensitivity of the LR model for the prognosis prediction of hospital-acquired Klebsiella pneumoniae infection was 94.7%; and the specificity was 65%. The prediction accuracy of the RF model was 89.6%; the true positive rate of the RF model was 92.1%; the false negative rate of the RF model was 7.9%; the false positive rate of the RF model was 21.4%; the true negative rate of the RF model was 78.6%; the sensitivity of the RF model for the prognosis prediction of hospital-acquired Klebsiella pneumoniae infection was 92.1%; and the specificity was 78.6%. ROC curve shows that the area under curve(AUC) of the LR model was 0.91, and that of the RF model was 0.95. CONCLUSION: The RF model has higher specificity, sensitivity, and accuracy for the prognostic prediction of hospital-acquired Klebsiella pneumoniae infection than the LR model and has greater clinical application prospects.

Rapid, accurate, and novel diagnostic technique for respiratory pathogens: Clinical application of loop-mediated isothermal amplification assay in older patients with pneumonia, a multicenter prospective observational study.

Background: Loop-mediated isothermal amplification (LAMP) is a novel nucleic acid amplification method using only one type of enzyme that can amplify DNA with high specificity, efficiency and rapidity under isothermal conditions. Chips for Complicated Infection Detection (CCID) is based on LAMP. This study translate CCID into clinical application and evaluate its diagnostic value for pneumonia. Methods: Eighty one older patients with pneumonia were prospectively enrolled from January 1 to July 23, 2021, and 57 sputum/airway secretion and 35 bronchoalveolar lavage fluid samples were collected and analyzed by CCID and conventional microbiological tests (CMTs). Samples were collected, transported, monitored, and managed by a multidisciplinary team using a sample management information system. Results: CCID turnaround time was 50 min, and the detection limit was 500 copies/reaction. The percentage of positive samples was significantly higher using CCID than CMTs, especially for Klebsiella pneumoniae (odds ratio [OR], 9.0; 95% confidence interval [CI], 1.1-70.5; p < 0.05), Enterococcus faecalis (OR, ∞; p < 0.01), Stenotrophomonas maltophilia (OR, ∞; p < 0.01), fungi (OR, 26.0; 95% CI, 3.6-190.0; p < 0.01), and viruses (CCID only; p < 0.01). In addition, the percentage of positive results was significantly higher using CCID than CMTs in patients who used antibiotics for more than 3 days (91.9% vs. 64.9%; p < 0.01). Analyzing clinical impact, 55 cases (59.8%) benefited from CCID. Conclusion: CCID allows the rapid and accurate detection of pneumonia in older patients. Moreover, this technique is less affected by previous antibiotic treatment and can improve patient care.

Risk Factors for and Clinical Outcomes of Carbapenem-Resistant Klebsiella pneumoniae Nosocomial Infections: A Retrospective Study in a Tertiary Hospital in Beijing, China.

PURPOSE: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections have been increasingly reported worldwide. We aimed to identify the risk factors for nosocomial CRKP infections and assess the clinical outcomes. PATIENTS AND METHODS: We conducted a case-control study with data collected from January 2016 to December 2018 in China. Controls were selected at a ratio of 1:1 from patients with nosocomial carbapenem-susceptible Klebsiella pneumonia (CSKP) infections. Risk factors for nosocomial CRKP infections and clinical outcomes were assessed with univariate and multivariate analyses. RESULTS: A total of one hundred forty-two patients with CRKP infections and one hundred forty-two patients with CSKP infections were enrolled in this study. Multivariate analysis showed that exposure to antibiotics within 3 months prior to admission (odds ratio OR, 2.585; 95% confidence interval [CI], 1.425-4.691; P=0.002), exposure to carbapenems (OR, 2.532; 95% CI, 1.376-4.660; P=0.003), exposure to fluoroquinolones (OR, 3.309; 95% CI, 1.326-8.257; P=0.010), and the presence of a nasogastric tube (OR, 2.796; 95% CI, 1.369-5.712; P=0.005) were independent risk factors for CRKP infections. The 30-day mortality rate in the CRKP group was 19.7%, while the in-hospital mortality rate was 28.9%. In the CRKP group, a higher creatinine level (OR, 1.009; 95% CI, 1.002-1.016; P = 0.013), being in shock at the time of a positive culture (OR, 4.454; 95% CI, 1.374-14.443; P = 0.013), and co-infection with other resistant bacteria (OR, 4.799; 95% CI, 1.229-18.740; P = 0.024) were independent predictors of in-hospital mortality in patients with CRKP infections. Kaplan-Meier curves showed that the CRKP group had a shorter survival time than the CSKP group. CONCLUSION: Nosocomial CRKP infection was associated with exposure to carbapenems and fluoroquinolones within 3 months prior to hospitalization and the presence of a nasogastric tube. Patients infected with CRKP had higher 30-day and in-hospital mortality rates. A higher creatinine level, shock and co-infection with other resistant bacteria were independent predictors of in-hospital mortality in patients with CRKP infections.

Identification of novel transcription factor-microRNA-mRNA co-regulatory networks in pulmonary large-cell neuroendocrine carcinoma.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) of the lung is a rare neuroendocrine neoplasm. Previous studies have shown that microRNAs (miRNAs) are widely involved in tumor regulation through targeting critical genes. However, it is unclear which miRNAs play vital roles in the pathogenesis of LCNEC, and how they interact with transcription factors (TFs) to regulate cancer-related genes. METHODS: To determine the novel TF-miRNA-target gene feed-forward loop (FFL) model of LCNEC, we integrated multi-omics data from Gene Expression Omnibus (GEO), Transcriptional Regulatory Relationships Unraveled by Sentence-Based Text Mining (TRRUST), Transcriptional Regulatory Element Database (TRED), and The experimentally validated microRNA-target interactions database (miRTarBase database). First, expression profile datasets for mRNAs (GSE1037) and miRNAs (GSE19945) were downloaded from the GEO database. Overlapping differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified through integrative analysis. The target genes of the FFL were obtained from the miRTarBase database, and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed on the target genes. Then, we screened for key miRNAs in the FFL and performed gene regulatory network analysis based on key miRNAs. Finally, the TF-miRNA-target gene FFLs were constructed by the hypergeometric test. RESULTS: A total of 343 DEGs and 60 DEMs were identified in LCNEC tissues compared to normal tissues, including 210 down-regulated and 133 up-regulated genes, and 29 down-regulated and 31 up-regulated miRNAs. Finally, the regulatory network of TF-miRNA-target gene was established. The key regulatory network modules included ETS1-miR195-CD36, TAOK1-miR7-1-3P-GRIA1, E2F3-miR195-CD36, and TEAD1-miR30A-CTHRC1. CONCLUSIONS: We constructed the TF-miRNA-target gene regulatory network, which is helpful for understanding the complex LCNEC regulatory mechanisms.

AI-assisted CT imaging analysis for COVID-19 screening: Building and deploying a medical AI system.

The sudden outbreak of novel coronavirus 2019 (COVID-19) increased the diagnostic burden of radiologists. In the time of an epidemic crisis, we hope artificial intelligence (AI) to reduce physician workload in regions with the outbreak, and improve the diagnosis accuracy for physicians before they could acquire enough experience with the new disease. In this paper, we present our experience in building and deploying an AI system that automatically analyzes CT images and provides the probability of infection to rapidly detect COVID-19 pneumonia. The proposed system which consists of classification and segmentation will save about 30%-40% of the detection time for physicians and promote the performance of COVID-19 detection. Specifically, working in an interdisciplinary team of over 30 people with medical and/or AI background, geographically distributed in Beijing and Wuhan, we are able to overcome a series of challenges (e.g. data discrepancy, testing time-effectiveness of model, data security, etc.) in this particular situation and deploy the system in four weeks. In addition, since the proposed AI system provides the priority of each CT image with probability of infection, the physicians can confirm and segregate the infected patients in time. Using 1,136 training cases (723 positives for COVID-19) from five hospitals, we are able to achieve a sensitivity of 0.974 and specificity of 0.922 on the test dataset, which included a variety of pulmonary diseases.

Features and Risk Factors for Paraneoplastic Autoimmune Multiorgan Syndrome in 145 Chinese Patients.

Paraneoplastic autoimmune multiorgan syndrome is a complex and deadly disease. We retrospectively reviewed the clinical features and risk factors for paraneoplastic autoimmune multiorgan syndrome in 145 Chinese patients. The most common neoplasm was Castleman disease (56%), and patients with Castleman disease tended to be younger (≤ 42 years old: 83% vs. 29%) and to have a greater proportions of lichen planus-like lesions (47% vs. 27%) and bronchiolitis obliterans (49% vs. 29%), compared to other neoplasm-associated patients. Among all 145 patients in the study, the survival rates were 84% at 1 year, 65% at 3 years, and 54% at 5 years. Kaplan-Meier curve analysis revealed that mortality was associated with older age (> 42 years), neoplasm type, labial lesions, and larger skin lesion area (> 17.5% of the body surface area). However, only older age and larger skin lesion area were independent factors associated with mortality in multivariate analysis. We suggest that patients with Castleman disease and paraneoplastic autoimmune multiorgan syndrome have many unique characteristics and the underlying risk factors for death require further exploration.

Clinical features of pediatric patients with COVID-19: a report of two family cluster cases.

BACKGROUND: Coronovirus disease 2019 (COVID-19) has spread rapidly across the globe. People of all ages are susceptible to COVID-19. However, literature reports on pediatric patients are limited. METHODS: To improve the recognition of COVID-19 infection in children, we retrospectively reviewed two confirmed pediatric cases from two family clusters. Both clinical features and laboratory examination results of the children and their family members were described. RESULTS: The two confirmed children only presented with mild respiratory or gastrointestinal symptoms. Both of them had normal chest CT images. After general and symptomatic treatments, both children recovered quickly. Both families had travel histories to Hubei Province. CONCLUSIONS: Pediatric patients with COVID-19 are mostly owing to family cluster or with a close contact history. Infected children have relatively milder clinical symptoms than infected adults. We should attach importance to early recognition, early diagnosis, and early treatment of infected children.

Thoracic ultrasound versus artificial pneumothorax in complications of medical thoracoscopy-a propensity score matching analysis.

BACKGROUND: Evaluation and location of the approaches is the key step of medical thoracoscopy. The previous standard for the step in many countries is artificial pneumothorax (AP). Recently, thoracic ultrasound (TU) has been considered as one of the choices for the development of technology. While there was a lack of data in investigating the complications of medical thoracoscopy locating approach with AP comparing TU. METHODS: A total of 108 patients who underwent medical thoracoscopy were retrospectively observed in Peking University First Hospital from January 2011 to April 2017, including 92 patients of the AP group and 16 patients of the TU group. Propensity score matching (PSM) was used to balance the covariance between the two groups. And the complications of the procedures between the groups were compared. RESULTS: Before PSM, there was one unbalanced covariates in the two groups. The overall complication rate was 7.6% (7/92) in the AP group, comparing 6.2% (1/16) in the TU group. There was no significant difference between the two groups (P=0.848). After balancing the covariate with 2:1 matched, the overall complication rate was 9.4% (3/32) in the AP group, comparing 6.2% (1/16) in the TU group. There was still no significant difference between the two groups (P=0.712). CONCLUSIONS: TU is a locating approach method which does not increase the complication rate comparing with AP. And it could be a good choice in medical thoracoscopy.

Relationship between Radiological Stages and Prognoses of Pneumocystis Pneumonia in Non-AIDS Immunocompromised Patients.

BACKGROUND: Although radiological features of pneumocystis pneumonia (PCP) in non-Acquired Immune Deficiency Syndrome (AIDS) immunocompromised patients have been reported by other authors, there were no studies on the radiological stages of PCP previously. This study aimed to elucidate the radiological stages and prognoses of PCP in non-AIDS immunocompromised patients. METHODS: Retrospective analysis of radiological manifestations and prognoses of 105 non-AIDS PCP immunocompromised patients from August 2009 to April 2016 was conducted. Chest radiograph was divided into three stages: early stage (normal or nearly normal chest radiograph), mid stage (bilateral pulmonary infiltrates), and late stage (bilateral pulmonary consolidations); chest high-resolution computed tomography (HRCT) was also divided into three stages: early stage (bilateral diffuse ground-glass opacity [GGO]), mid stage (bilateral diffuse GGO and patchy consolidations), and late stage (bilateral diffuse consolidations). RESULTS: The case fatality rate (CFR) of all patients was 34.3% (36/105), all of them took routine chest X-ray (CXR), and 84 underwent chest CT examinations. According to the CXR most near the beginning of anti-PCP therapy, 18 cases were at early stage and CFR was 0 (0/18, P< 0.01), 50 cases were at mid stage and CFR was 28.0% (14/50, P> 0.05), and 37 cases were at late stage and CFR was 59.5% (22/37, P< 0.01). According to the chest HRCT most near the beginning of anti-PCP therapy, 40 cases were at early stage and CFR was 20.0% (8/40, P> 0.05), 34 cases were at mid stage and CFR was 47.1% (16/34, P> 0.05), and 10 cases were at late stage and CFR was 80.0% (8/10, P< 0.05); barotrauma, including pneumothorax, pneumomediastinum, and pneumohypoderma, was found in 18 cases and the CFR was 77.8% (14/18, P< 0.01). CONCLUSIONS: Based on the radiological manifestations, the course of PCP in non-AIDS immunocompromised patients can be divided into three stages: early stage, mid stage, and late stage. The prognoses of patients treated at early stage are good, and those at late stage are poor. Furthermore, the CFR of patients with barotrauma is high.