Causal association of circulating cytokines with the risk of lung cancer: a Mendelian randomization study.

Background: Lung cancer is the deadliest and most prevalent malignancy worldwide. While smoking is an established cause, evidence to identify other causal factors remains lacking. Current research indicates chronic inflammation is involved in tumorigenesis and cancer development, though the specific mechanisms underlying the role of inflammatory cytokines in lung cancer pathogenesis remain unclear. This study implemented Mendelian randomization (MR) analysis to investigate the causal effects of circulating cytokines on lung cancer development. Methods: We performed a two-sample MR analysis in Europeans utilizing publicly available genome-wide association study summary statistics. Single nucleotide polymorphisms significantly associated with cytokine were selected as genetic instrumental variables. Results: Genetically predicted levels of the chemokine interleukin-18 (IL-18) (OR = 0.942, 95% CI: 0.897-0.990, P = 0.018) exerted significant negative causal effects on overall lung cancer risk in this analysis. Examining specific histologic subtypes revealed further evidence of genetic associations. Stem cell factor (SCF) (OR = 1.150, 95% CI: 1.021-1.296, P = 0.021) and interleukin-1beta (IL-1ß) (OR = 1.152, 95% CI: 1.003-1.325, P = 0.046) were positively associated with lung adenocarcinoma risk, though no inflammatory factors showed causal links to squamous cell lung cancer risk. Stratified by smoking status, interferon gamma-induced protein 10 (IP-10) (OR = 0.861, 95% CI: 0.781-0.950, P = 0.003) was inversely associated while IL-1ß (OR = 1.190, 95% CI: 1.023-1.384, P = 0.024) was positively associated with lung cancer risk in ever smokers. Among never smokers, a positive association was observed between lung cancer risk and SCF (OR = 1.474, 95% CI: 1.105-1.964, P = 0.008). Importantly, these causal inferences remained robust across multiple complementary MR approaches, including MR-Egger, weighted median, weighted mode and simple mode regressions. Sensitivity analyses also excluded potential bias stemming from pleiotropy. Conclusion: This MR study found preliminary evidence that genetically predicted levels of four inflammatory cytokines-SCF, IL-1ß, IL-18, and IP-10-may causally influence lung cancer risk in an overall and subtype-specific manner, as well as stratified by smoking status. Identifying these cytokine pathways that may promote lung carcinogenesis represents potential new targets for the prevention, early detection, and treatment of this deadly malignancy.

Perioperative fluid balance and early acute kidney injury after lung transplantation.

BACKGROUND: Postoperative acute kidney injury (AKI) after lung transplantation (LTx) is an important factor affecting the short-term outcomes. The focus item of transplantation centers is how to improve the incidence of AKI through optimal management during the perioperative period. OBJECTIVE: The purpose of the study is to investigate the influence of perioperative volume in the development of early AKI following LTx. METHOD: The study involved patients who had undergone LTx between October 2018 to December 2021 at China-Japan Friendship Hospital in Beijing. The patients were monitored for AKI occurring within 72 hours after LTx, as well as the renal outcomes within 30 days. The perioperative volumes were compared and analyzed to determine the impact on various clinical outcomes. RESULTS: 248 patients were enrolled in the study ultimately, with almost half of them (49.6 %) experiencing AKI. 48.8 % of AKI patients received continuous renal replacement therapy (CRRT), with 57.7 % recovered by the end of the 30-day follow-up period. A J-shaped relationship was demonstrated between perioperative volume and AKI incidence. Moreover, maintaining a positive fluid balance would increase the 30-day mortality and lead to poor renal outcomes. CONCLUSION: Perioperative volume is an independent risk factor of early AKI after LTx. Positive fluid balance increases the risk of AKI, 30-day mortality, and adverse renal prognosis. The LTx recipients may benefit from a relatively restrict fluid strategy during and after the lung transplantation.

A Novel Approach for the Detection and Severity Grading of Chronic Obstructive Pulmonary Disease Based on Transformed Volumetric Capnography.

Chronic Obstructive Pulmonary Disease (COPD), as the third leading cause of death worldwide, is a major global health issue. The early detection and grading of COPD are pivotal for effective treatment. Traditional spirometry tests, requiring considerable physical effort and strict adherence to quality standards, pose challenges in COPD diagnosis. Volumetric capnography (VCap), which can be performed during natural breathing without requiring additional compliance, presents a promising alternative tool. In this study, the dataset comprised 279 subjects with normal pulmonary function and 148 patients diagnosed with COPD. We introduced a novel quantitative analysis method for VCap. Volumetric capnograms were converted into two-dimensional grayscale images through the application of Gramian Angular Field (GAF) transformation. Subsequently, a multi-scale convolutional neural network, CapnoNet, was conducted to extract features and facilitate classification. To improve CapnoNet's performance, two data augmentation techniques were implemented. The proposed model exhibited a detection accuracy for COPD of 95.83%, with precision, recall, and F1 measures of 95.21%, 95.70%, and 95.45%, respectively. In the task of grading the severity of COPD, the model attained an accuracy of 96.36%, complemented by precision, recall, and F1 scores of 88.49%, 89.99%, and 89.15%, respectively. This work provides a new perspective for the quantitative analysis of volumetric capnography and demonstrates the strong performance of the proposed CapnoNet in the diagnosis and grading of COPD. It offers direction and an effective solution for the clinical application of capnography.

Renal Replacement Therapy as a New Indicator of Voriconazole Clearance in a Population Pharmacokinetic Analysis of Critically Ill Patients.

AIMS: The pharmacokinetic (PK) profiles of voriconazole in intensive care unit (ICU) patients differ from that in other patients. We aimed to develop a population pharmacokinetic (PopPK) model to evaluate the effects of using extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and those of various biological covariates on the voriconazole PK profile. METHODS: Modeling analyses of the PK parameters were conducted using the nonlinear mixed-effects modeling method (NONMEM) with a two-compartment model. Monte Carlo simulations (MCSs) were performed to observe the probability of target attainment (PTA) when receiving CRRT or not under different dosage regimens, different stratifications of quick C-reactive protein (qCRP), and different minimum inhibitory concentration (MIC) ranges. RESULTS: A total of 408 critically ill patients with 746 voriconazole concentration-time data points were included in this study. A two-compartment population PK model with qCRP, CRRT, creatinine clearance rate (CLCR), platelets (PLT), and prothrombin time (PT) as fixed effects was developed using the NONMEM. CONCLUSIONS: We found that qCRP, CRRT, CLCR, PLT, and PT affected the voriconazole clearance. The most commonly used clinical regimen of 200 mg q12h was sufficient for the most common sensitive pathogens (MIC ≤ 0.25 mg/L), regardless of whether CRRT was performed and the level of qCRP. When the MIC was 0.5 mg/L, 200 mg q12h was insufficient only when the qCRP was <40 mg/L and CRRT was performed. When the MIC was ≥2 mg/L, a dose of 300 mg q12h could not achieve ≥ 90% PTA, necessitating the evaluation of a higher dose.

Carbapenem-Resistant Pseudomonas aeruginosa Infection and Mixed Infections Are Risk Factors for Poor Outcome After Lung Transplant.

OBJECTIVES: In this study, we analyzed the effects of carbapenem-resistant Pseudomonas aeruginosa infection and mixed infection on the perioperative prognosis of lung transplant recipients and studied statistics on antibiotic resistance in P aeruginosa. MATERIALS AND METHODS: This was a retrospective casecontrol study. We collected data on lung transplant recipients with combined lower respiratory tract P aeruginosa infection within 48 hours after lung transplant at the China-Japan Friendship Hospital from August 2018 to April 2022. We grouped recipients according to P aeruginosa resistance to carbapenem antibiotics and summarized the clinical characteristics of carbapenem-resistant P aeruginosa infection. We analyzed the effects of carbapenemresistant P aeruginosa infection and mixed infections on all-cause mortality 30 days after lung transplant by Cox regression. We used the Kaplan-Meier method to plot survival curves. RESULTS: Patients in the carbapenem-resistant P aeruginosa group had a higher all-cause mortality rate than those in the carbapenem-sensitive P aeruginosa group at both 7 days (6 patients [22.3%] vs 2 patients [4.5%]; P = .022) and 30 days (12 patients [44.4%] vs 7 patients [15.9%]; P = .003) after lung transplant. In multivariate analysis, both carbapenemresistant P aeruginosa infection and P aeruginosa combined with bacterial infection were independent risk factors for death 30 days after transplant in lung transplant recipients (P < .05). In subgroup analysis, carbapenem-resistant P aeruginosa combined with bacterial infection increased the risk of death 30 days after transplant in lung transplant recipients compared with carbapenem-sensitive P aeruginosa combined with bacterial infection (12 patients [60%] vs 6 patients [19.4%]; P < .001). CONCLUSIONS: Combined lower respiratory tract carbapenem-resistant P aeruginosa infection and P aeruginosa combined with bacterial infection early after lung transplant increased the risk of 30-day mortality after lung transplant.

Association between the lung microbiome and perioperative prognosis in lung transplant recipients.

RATIONALE: Studies have confirmed that the lung microbiome of lung transplant recipients is altered and serves as a prognostic indicator for long-term mortality. Other studies reported that the lung microbiome affects host immunity and the transcriptome. However, the lung microbiome composition at the early post-transplant period following lung transplantation is unclear, and the relationship of the lung microbiome with pulmonary immunity and the host transcriptome is also not well understood. OBJECTIVES: We hypothesize that changes in the lung microbiome composition in the early post-transplant period may have a predictive value for perioperative outcomes following lung transplantation and that the lung microbiome is correlated with pulmonary immunity and the host transcriptome. Thus, this prospective study aimed at observing the lung microbiome composition in the early post-transplant period and the impact of the lung microbiome on pulmonary cytokines and the host transcriptome. Our findings will help us gain a comprehensive understanding of the distribution and significance of the lung microbiome in the early post-transplant period. METHODS: An observational study was conducted to identify the lung microbiome and the host transcriptome characteristics using next-generation sequencing. Luminex was employed for quantifying alveolar cytokines. Spearman's correlation analysis was utilized to assess the impact of the lung microbiome on pulmonary immunity and differentially expressed genes in patients who died perioperatively after lung transplantation. RESULTS: Patients with poor perioperative outcomes showed an increase in Mycoplasma and Arcobacter, a decrease of Gemella, and increased interleukin (IL)-10, IL-1ß, and tumor necrosis factor (TNF)-α concentration. The lung microbiome correlates with lung immunity in lung transplant recipients. In the death group, the function of differentially expressed genes is associated with cell apoptosis, and promoting TNF production is upregulated. The lung microbiome is related to differentially expressed genes between the two groups. CONCLUSIONS: The lung microbiome and cytokines can be considered as potential biomarkers for early prognosis in lung transplant recipients. The lung microbiome is associated with both lung immunity and differentially expressed genes in lung transplant recipients.

Rutin targets AKT to inhibit ferroptosis in ventilator-induced lung injury.

Our previous research confirmed that rutin reduced ventilator-induced lung injury (VILI) in mice. Ferroptosis has been reported to participate in the pathogenic process of VILI. We will explore whether rutin inhibits ferroptosis to alleviate VILI. A mouse model of VILI was constructed with or without rutin pretreatment to perform a multiomics analysis. Hematoxylin-eosin (HE) staining and transmission electron microscopy were used to evaluate lung injury in VILI mice. Dihydroethidium (DHE) staining and the malondialdehyde (MDA) and superoxide dismutase (SOD) levels were detected. Molecular docking was performed to determine the binding affinity between rutin and ferroptosis-related proteins. Western blot analysis, real-time PCR (RT-PCR) and immunohistochemical (IHC) staining were conducted to detect the expression levels of GPX4, XCT, ACSL4, FTH1, AKT and p-AKT in lung tissues. Microscale thermophoresis (MST) was used to evaluate the binding between rutin and AKT1. Transcriptomic and proteomic analyses showed that ferroptosis may play a key role in VILI mice. Metabolomic analysis demonstrated that rutin may affect ferroptosis via the AKT pathway. Molecular docking analysis indicated that rutin may regulate the expression of ferroptosis-related proteins. Moreover, rutin upregulated GPX4 expression and downregulated the expression of XCT, ACSL4 and FTH1 in the lung tissues. Rutin also increased the ratio of p-AKT/AKT and p-AKT expression. MST analysis showed that rutin binds to AKT1. Rutin binds to AKT to activate the AKT signaling pathway, contributing to inhibit ferroptosis, thus preventing VILI in mice. Our study elucidated a possible novel strategy of involving the use of rutin for preventing VILI.

Association between red blood cell distribution width-to-platelet ratio and post-discharge readmission rate in patients with heart failure: A retrospective cohort study.

Background: To date, no studies have investigated the association between red blood cell distribution width (RDW)-to-platelet ratio (RPR) and readmission rates among patients with heart failure (HF). As such, the present study aimed to examine the relationship between RPR and readmission rates in patients with HF. Methods: Data for this study were obtained from the Fourth People's Hospital (Zigong, Sichuan Province, China). Patients were diagnosed with HF in accordance with European Society of Cardiology criteria. The primary outcome was the 28-day readmission rate. Various logistic regression models were constructed to explore the association between RPR and the 28-day readmission rate. Results: The study comprised 1978 patients with HF, with a 28-day readmission rate of 6.98%. RPR emerged as an independent risk factor for 28-day readmission, evidenced by consistent results across the various regression-adjusted models. The covariate-adjusted propensity score model demonstrated that every 0.1 increase in RPR was associated with an 8.2% increase in 28-day readmission rate (odds ratio [OR] 1.082 [95% confidence interval (CI) 1.012-1.158]; P = 0.0212). Similarly, each 0.1 change in RPR was associated with a 9.8% (OR 1.098 [95% CI 1.014-1.188]) and 7.3% (OR 1.073 [95% CI 0.991-1.161]) increase in 3- and 6-month readmission rates, respectively. However, RPR was not statistically associated with the 6-month readmission rate. Curve fit plots illustrated a nonlinear positive correlation between RPR and 28-day, and 3- and 6-month readmissions. Moreover, the effects of RPR on 28-day, and 3- and 6-month readmission rates remained robust across subgroup variables in stratified analysis. Finally, the effect sizes of pooled multiply imputed data were consistent with the original data, suggesting robust results. Conclusion: RPR was an independent risk factor for 28-day readmission among patients with HF and also demonstrated modest predictive value for readmissions at 3 and 6 months, despite being non-significant for the 6-month readmission rate. Early identification of patients with HF with elevated RPR would facilitate management and may confer favorable effects on prognosis.

Mediating Effect of Tobacco Dependence on the Association Between Maternal Smoking During Pregnancy and Chronic Obstructive Pulmonary Disease: Case-Control Study.

BACKGROUND: Maternal smoking during pregnancy (MSDP) is a known risk factor for offspring developing chronic obstructive pulmonary disease (COPD), but the underlying mechanism remains unclear. OBJECTIVE: This study aimed to explore whether the increased COPD risk associated with MSDP could be attributed to tobacco dependence (TD). METHODS: This case-control study used data from the nationwide cross-sectional China Pulmonary Health study, with controls matched for age, sex, and smoking status. TD was defined as smoking within 30 minutes of waking, and the severity of TD was assessed using the Fagerstrom Test for Nicotine Dependence. COPD was diagnosed when the ratio of forced expiratory volume in 1 second to forced vital capacity was <0.7 in a postbronchodilator pulmonary function test according to the 2017 Global Initiative for Chronic Obstructive Lung Disease criteria. Logistic regression was used to examine the correlation between MSDP and COPD, adjusting for age, sex, BMI, educational attainment, place of residence, ethnic background, occupation, childhood passive smoking, residential fine particulate matter, history of childhood pneumonia or bronchitis, average annual household income, and medical history (coronary heart disease, hypertension, and diabetes). Mediation analysis examined TD as a potential mediator in the link between MSDP and COPD risk. The significance of the indirect effect was assessed through 1000 iterations of the "bootstrap" method. RESULTS: The study included 5943 participants (2991 with COPD and 2952 controls). Mothers of the COPD group had higher pregnancy smoking rates (COPD: n=305, 10.20%; controls: n=211, 7.10%; P<.001). TD was more prevalent in the COPD group (COPD: n=582, 40.40%; controls: n=478, 33.90%; P<.001). After adjusting for covariates, MSDP had a significant effect on COPD (ß=.097; P<.001). There was an association between MSDP and TD (ß=.074; P<.001) as well as between TD and COPD (ß=.048; P=.007). Mediation analysis of TD in the MSDP-COPD association showed significant direct and indirect effects (direct: ß=.094; P<.001 and indirect: ß=.004; P=.03). The indirect effect remains present in the smoking population (direct: ß=.120; P<.001 and indirect: ß=.002; P=.03). CONCLUSIONS: This study highlighted the potential association between MSDP and the risk of COPD in offspring, revealing the mediating role of TD in this association. These findings contribute to a deeper understanding of the impact of prenatal tobacco exposure on lung health, laying the groundwork for the development of relevant prevention and treatment strategies.

The effect of adoptive transferring myeloid-derived suppressor cells in ventilator-induced lung injury mice.

The effects of adoptive transferring myeloid-derived suppressor cells (MDSCs) to mice with ventilator-induced lung injury (VILI) are unclear. Our objective was to investigate the effects of adoptively transferring MDSCs in VILI. The mouse model was created by introducing mechanical ventilation through a high tidal volume of 20 ml/kg for 4 h. Inflammation-induced MDSCs (iMDSCs) were collected from the bone marrow of mice with cecal ligation and puncture. iMDSCs were administrated through retrobulbar angular vein 1 h before the mechanical ventilation. The control group was anesthetized and maintained spontaneous respiration. After the termination of mechanical ventilation, bronchoalveolar lavage fluid (BALF) and lung samples 6 h were collected. The concentrations of BALF protein, levels of inflammatory mediators, and white blood cells were all significantly decreased in mice treated with iMDSCs. Histological examinations indicated reduced lung damage after iMDSCs treatment. Moreover, adoptive transfer of iMDSCs could reduce CD4+ T-cell counts and inhibit its inflammatory cytokine secretion. iMDSCs treatment was found to had no immunostimulatory effects or cause secondary infections in mice. In conclusion, MDSCs might be a potential targeted therapy for alleviating the inflammatory response of VILI mice in a T-cell dependent manner.

Risk factors and the value of microbiological examinations of COVID-19 associated pulmonary aspergillosis in critically ill patients in intensive care unit: the appropriate microbiological examinations are crucial for the timely diagnosis of CAPA.

Introduction: During the Omicron pandemic in China, a significant proportion of patients with Coronavirus Disease 2019 (COVID-19) associated pulmonary aspergillosis (CAPA) necessitated admission to intensive care unit (ICU) and experienced a high mortality. To explore the clinical risk factors and the application/indication of microbiological examinations of CAPA in ICU for timely diagnosis are very important. Methods: This prospective study included patients with COVID-19 admitted to ICU between December 1, 2022, and February 28, 2023. The clinical data of influenza-associated pulmonary aspergillosis (IAPA) patients from the past five consecutive influenza seasons (November 1, 2017, to March 31, 2022) were collected for comparison. The types of specimens and methods used for microbiological examinations were also recorded to explore the efficacy in early diagnosis. Results: Among 123 COVID-19 patients, 36 (29.3%) were diagnosed with probable CAPA. CAPA patients were more immunosuppressed, in more serious condition, required more advanced respiratory support and had more other organ comorbidities. Solid organ transplantation, APACHEII score ≥20 points, 5 points ≤SOFA score <10 points were independent risk factors for CAPA. Qualified lower respiratory tract specimens were obtained from all patients, and 84/123 (68.3%) patients underwent bronchoscopy to obtain bronchoalveolar lavage fluid (BALF) specimens. All patients' lower respiratory tract specimens underwent fungal smear and culture; 79/123 (64.2%) and 69/123 (56.1%) patients underwent BALF galactomannan (GM) and serum GM detection, respectively; metagenomic next-generation sequencing (mNGS) of the BALF was performed in 62/123 (50.4%) patients. BALF GM had the highest diagnostic sensitivity (84.9%), the area under the curve of the mNGS were the highest (0.812). Conclusion: The incidence of CAPA was extremely high in patients admitted to the ICU. CAPA diagnosis mainly depends on microbiological evidence owing to non-specific clinical manifestations, routine laboratory examinations, and CT findings. The bronchoscopy should be performed and the BALF should be obtained as soon as possible. BALF GM are the most suitable microbiological examinations for the diagnosis of CAPA. Due to the timely and accuracy result of mNGS, it could assist in early diagnosis and might be an option in critically ill CAPA patients.

High-flow nasal cannula may prolong the length of hospital stay in patients with hypercapnic acute COPD exacerbation.

BACKGROUND: High-flow nasal cannula (HFNC) is increasingly used in patients with acute exacerbation of COPD (AECOPD). We aimed to confirm whether the baseline bicarbonate is an independent predictor of outcomes in patients with hypercapnic AECOPD receiving HFNC. METHODS: This was a secondary analysis of a multicentre randomised trial that enrolled 330 patients with non-acidotic hypercapnic AECOPD supported by HFNC or conventional oxygen treatment (COT). We compared the length of stay (LOS) in hospital and the rate of non-invasive positive pressure ventilation (NPPV) use according to baseline bicarbonate levels using the log-rank test or Cox proportional hazard model. RESULTS: In the high bicarbonate subgroup (n = 165, bicarbonate 35.0[33.3-37.9] mmol/L, partial pressure of arterial carbon dioxide [PaCO2] 56.8[52.0-62.8] mmHg), patients supported by HFNC had a remarkably prolonged LOS in hospital when compared to COT (HR 1.59[1.16-2.17], p = 0.004), whereas patients in the low bicarbonate subgroup (n = 165, bicarbonate 28.8[27.0-30.4] mmol/L, PaCO2 48.0[46.0-50.0] mmHg) had a comparable LOS in hospital regardless of respiratory support modalities. The rate of NPPV use in patients with high baseline bicarbonate level was significantly higher than that in patients with low baseline bicarbonate level (19.4 % vs. 3.0 %, p < 0.0001). Patients with high bicarbonate level in HFNC group had a lower rate of NPPV use compared to COT group (15.4 % vs. 23.0 %, p = 0.217). CONCLUSIONS: Among patients with non-acidotic hypercapnic AECOPD with high baseline bicarbonate level, HFNC is significantly associated with a prolonged LOS in hospital, which may be due to the reduced escalation of NPPV treatment. TRIAL REGISTRATION: clinicaltrials.gov (NCT03003559).

Clinical and Temporal Radiological Findings from Critical Patients with COVID-19 Pneumonia: A Descriptive Study.

BACKGROUND: In late December 2019, Wuhan, the capital of Hubei Province, China, became the center of an outbreak of pneumonia caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). INTRODUCTION: The radiological changes in the lungs of critical people with coronavirus disease 2019 (COVID-19) pneumonia at different times have not been fully characterized. We aim to describe the computed tomography findings of patients with critical COVID-19 pneumonia at different disease stages. METHODS: Clinical and laboratory features of critical patients were assessed. CT scans were assigned to groups 1, 2, 3, or 4 based on the interval from symptom onset (within 2 weeks; ≥ 2-4 weeks; ≥ 4-6 weeks; or ≥ 6 weeks, respectively). Imaging features were analyzed and compared across the four groups. Total CT scores, corresponding periods of laboratory findings, and glucocorticoid dosages during the imaging intervals were longitudinally observed in five patients with complete data. RESULTS: All 11 critical patients (median age: 60 years [42-69]) underwent a total of 40 CT examinations, and the acquisition times ranged from 1-59 days after symptom onset. Median total CT scores were 18 (9-25.25); 44.5 (42.88-47.62); 43.75 (38.62-49.38); and 42 (32.25-53.25) in groups 1, 2, 3, and 4, respectively. The observed lesions were mainly bilateral (37 [92.5%]). The median values of involved lung segments were 10.5 (4.5-13.5); 17 (16-18.5); 18 (18-19.5); and 18 (18-19) in groups 1-4, respectively. The predominant patterns of observed abnormalities were ground-glass opacities (GGO) (9 [90%]); GGO with reticulation and mixed patterns (3 [37.5%] for both); GGO with consolidation (3 [30%]); and GGO with reticulation (8 [66.7%]) in groups 1-4, respectively. Patients developed fibrotic manifestations at later stages. CONCLUSION: Critical patients with COVID-19 infection generally presented with temporally changing abnormal CT features from focal unilateral to diffuse bilateral GGO and consolidation that progressed to or coexisted with reticulation in the long term after symptom onset. Low-dose glucocorticoids may be effective in patients with interstitial changes on CT findings.

The role of lung microbiota in primary graft dysfunction in lung transplant recipients.

BACKGROUND: Recent studies have shown that the lung microbiota is altered in critically ill patients and predicts clinical outcomes. Primary graft dysfunction (PGD) is a common complication and a leading cause of death within 1 month of lung transplantation, but the clinical significance of changes in the lung bacterial community during PGD is unclear. The aim of this study was to determine the contribution of the lung microbiota to the development and course of severe PGD. METHODS: We conducted a retrospective study to characterize the lung microbiota of 32 lung transplant patients with combined PGD using next-generation sequencing of bronchoalveolar lavage samples. The relationship between lung flora dysbiosis and lung immunity in PGD was assessed by quantification of alveolar cytokines. The contribution of microbiota characteristics to patient outcomes was assessed by estimating overall survival. RESULTS: Patients diagnosed with PGD grade 3 showed a reduction in alpha diversity, driven by a significant increase in the abundance of the genera Modestobacter, Scardovia and Selenomonas, and a reduction in the proportion of the genera Klebsiella and Oribacterium. Alpha diversity of the lung microbiota in PGD3 patients was negatively correlated with BALF interleukin (IL)-2 (r = -.752, p < .05). In addition, bacterial diversity in the lung microbiota of non-survivors was lower than that of survivors (p = .041). CONCLUSIONS: There is variation in the lung microbiota of PGD grade 3 patients and dysbiosis of the lung microbiota is associated with lung immunity. The lung microbiota has potential in the diagnosis and treatment of PGD grade 3.

Rutin alleviates ventilator-induced lung injury by inhibiting NLRP3 inflammasome activation.

Whether rutin relieves ventilator-induced lung injury (VILI) remains unclear. Here, we used network pharmacology, bioinformatics, and molecular docking to predict the therapeutic targets and potential mechanisms of rutin in the treatment of VILI. Subsequently, a mouse model of VILI was established to confirm the effects of rutin on VILI. HE staining showed that rutin alleviated VILI. TUNEL staining showed that rutin reduced apoptosis in the lung tissue of mice with VILI, and the same change was observed in the ratio of Bax/Bcl2. Furthermore, rutin reduced the expression of NLRP3, ASC, Caspase1, IL1ß, and IL18 in the lung tissues of mice with VILI. Mechanistically, rutin suppressed the TLR4/NF-κB-P65 pathway, which promoted the M1 to M2 macrophage transition and alleviated inflammation in mice with VILI. Rutin relieved NLRP3 inflammasome activation by regulating M1/M2 macrophage polarization and inhibiting the activation of the TLR4/NF-κB-P65 pathway, resulting in the amelioration of VILI in mice.

Coinfection and superinfection in ICU critically ill patients with severe COVID-19 pneumonia and influenza pneumonia: are the pictures different?

Background: Similar to influenza, coinfections and superinfections are common and might result in poor prognosis. Our study aimed to compare the characteristics and risks of coinfections and superinfections in severe COVID-19 and influenza virus pneumonia. Methods: The data of patients with COVID-19 and influenza admitted to the intensive care unit (ICU) were retrospectively analyzed. The primary outcome was to describe the prevalence and pathogenic distribution of coinfections/ICU-acquired superinfections in the study population. The secondary outcome was to evaluate the independent risk factors for coinfections/ICU-acquired superinfections at ICU admission. Multivariate analysis of survivors and non-survivors was performed to investigate whether coinfections/ICU-acquired superinfections was an independent prognostic factor. Results: In the COVID-19 (n = 123) and influenza (n = 145) cohorts, the incidence of coinfections/ICU-acquired superinfections was 33.3%/43.9 and 35.2%/52.4%, respectively. The most common bacteria identified in coinfection cases were Enterococcus faecium, Pseudomonas aeruginosa, and Acinetobacter baumannii (COVID-19 cohort) and A. baumannii, P. aeruginosa, and Klebsiella pneumoniae (influenza cohort). A significant higher proportion of coinfection events was sustained by Aspergillus spp. [(22/123, 17.9% in COVID-19) and (18/145, 12.4% in influenza)]. The COVID-19 group had more cases of ICU-acquired A. baumannii, Corynebacterium striatum and K. pneumoniae. A. baumannii, P. aeruginosa, and K. pneumoniae were the three most prevalent pathogens in the influenza cases with ICU-acquired superinfections. Patients with APACHE II ≥18, CD8+ T cells ≤90/µL, and 50 < age ≤ 70 years were more susceptible to coinfections; while those with CD8+ T cells ≤90/µL, CRP ≥120 mg/L, IL-8 ≥ 20 pg./mL, blood glucose ≥10 mmol/L, hypertension, and smoking might had a higher risk of ICU-acquired superinfections in the COVID-19 group. ICU-acquired superinfection, corticosteroid administration for COVID-19 treatment before ICU admission, and SOFA score ≥ 7 were independent prognostic factors in patients with COVID-19. Conclusion: Patients with COVID-19 or influenza had a high incidence of coinfections and ICU-acquired superinfections. The represent agents of coinfection in ICU patients were different from those in the general ward. These high-risk patients should be closely monitored and empirically treated with effective antibiotics according to the pathogen.

Clinical characteristics and prognosis of pneumonia-related bloodstream infections in the intensive care unit: a single-center retrospective study.

Background: Bloodstream infections (BSI) are one of the most severe healthcare-associated infections in intensive care units (ICU). However, there are few studies on pneumonia-related BSI (PRBSI) in the ICU. This study aimed to investigate the clinical and prognostic characteristics of patients with PRBSI in the ICU and to provide a clinical basis for early clinical identification. Methods: We retrospectively collected data from patients with bacterial BSI in a single-center ICU between January 1, 2017, and August 31, 2020. Clinical diagnosis combined with whole-genome sequencing (WGS) was used to clarify the diagnosis of PRBSI, and patients with PRBSI and non-PRBSI were analyzed for clinical features, prognosis, imaging presentation, and distribution of pathogenic microorganisms. Results: Of the 2,240 patients admitted to the MICU, 120 with bacterial BSI were included in this study. Thirty-two (26.7%) patients were identified as having PRBSI based on the clinical diagnosis combined with WGS. Compared to patients without PRBSI, those with PRBSI had higher 28-day mortality (81.3 vs.51.1%, p = 0.003), a higher total mortality rate (93.8 vs. 64.8%, p = 0.002), longer duration of invasive mechanical ventilation (median 16 vs. 6 days, p = 0.037), and prolonged duration of ICU stay (median 21 vs. 10 days, p = 0.004). There were no differences in other baseline data between the two groups, but patients with PRBSI had extensive consolidation on chest radiographs and significantly higher Radiographic Assessment of Lung Edema scores (mean 35 vs. 24, p < 0.001). The most common causative organisms isolated in the PRBSI group were gram-negative bacteria (n = 31, 96.9%), with carbapenem-resistant gram-negative bacteria accounting for 68.8% (n = 22) and multidrug-resistant bacteria accounting for 81.3% (n = 26). Conclusion: Pneumonia-related BSI is an important component of ICU-BSI and has a poor prognosis. Compared to non-PRBSI, patients with PRBSI do not have typical clinical features but have more severe lung consolidation lesions, and should be alerted to the possibility of their occurrence when combined with pulmonary gram-negative bacterial infections, especially carbapenem-resistant bacteria. Further multicenter, large-sample studies are needed to identify the risk factors for the development of PRBSI and prevention and treatment strategies.

Extracorporeal membrane oxygenation in immunocompromised patients with acute respiratory failure: A retrospective cohort study.

BACKGROUND: The clinical indications of extracorporeal membrane oxygenation (ECMO) in immunosuppressed patients are not clear. This study aimed to analyse the effectiveness of ECMO and to identify the risk factors for the mortality of ECMO in immunocompromised patients with acute respiratory failure. METHODS: This retrospective, cohort study included 46 confirmed immunocompromised patients with acute hypoxemic respiratory failure treated with ECMO between July 2014 and August 2020. The clinical features and outcomes of the survival group and the non-survival group were statistically analysed. RESULTS: The mean age of the enrolled patients was 60.0 (50.0, 66.0) years; male patients accounted for 60.9% of patients, and the mean CD4 level was 213 cells/µL (150.3, 325.3). The hospital mortality rate of the cohort was 67.4% (31/46 patients). Patients in the survival group showed a higher rate of receiving awake ECMO (11/15 vs. 4/31; p = 0.006), a lower rate of acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT) (1/15 vs. 12/31; p = 0.035), fewer platelet transfusion units (0/15 vs. 2/31 units; p = 0.039) and a lower rate of ventilator-associated pneumonia (2/15 vs. 19/31; p = 0.006). In a multivariate Cox regression analysis model, intubated ECMO (hazard ratio = 1.77, 95% confidence interval: 1.34-2.32, p < 0.001) and AKI requiring CRRT (1.37, 95% confidence interval: 1.14-1.61, p = 0.003) were identified as independent risk factors for mortality. CONCLUSIONS: In-hospital mortality has remained high in ECMO-treated immunocompromised patients with acute respiratory failure. Intubated ECMO and AKI receiving CRRT during ECMO treatment may predict ECMO failure in immunocompromised patients with ARF. A primarily awake ECMO strategy seems feasible in some selected immunocompromised patients.

The association between early fluid strategy and prognosis of acute respiratory distress syndrome: A post hoc study of CHARDS.

We aimed to assess general fluid management in China and evaluate the association between fluid balance and survival outcomes in acute respiratory distress syndrome (ARDS) patients. A retrospective, multicenter study including ARDS patients was conducted. We described the fluid management of ARDS patients in China. Furthermore, clinical characteristics and outcomes of patients subdivided by cumulative fluid balance were also analyzed. Multivariable logistic regression analysis was performed with hospital mortality as the outcome. From June 2016 to February 2018, 527 ARDS patients were included in our study. The mean cumulative fluid balance was 1669 (-1101 to 4351) mL in the first 7 day after intensive care unit (ICU) admission. Patients were divided into four groups based on cumulative fluid balance of the first 7 day after ICU admission: Group I (≤0 L), Group II (>0 L, ≤3 L), Group III (>3 L, ≤5 L), and Group IV (>5 L). Significantly lower hospital mortality was observed in patients with a lower cumulative fluid balance on day 7 of ICU admission (20.5% in Group I vs. 32.8% in Group II, 38.5% in Group III, and 50% in Group IV, p < 0.001). A lower fluid balance is associated with lower hospital mortality in patients with ARDS. However, a large-scale and well-designed randomized controlled trial is needed in the future.

Incidence, outcomes and risk factors of barotrauma in veno-venous extracorporeal membrane oxygenation for acute respiratory distress syndrome.

BACKGROUND: Although acute respiratory distress syndrome (ARDS) patients are provided a lung rest strategy during extracorporeal membrane oxygenation (ECMO) treatment, the exact conditions of barotrauma is unclear. Therefore, we analyzed the epidemiology and risk factors for barotrauma in ARDS patients using ECMO in a single, large ECMO center in China. METHODS: A retrospective analysis was performed on 127 patients with ARDS received veno-venous (VV) ECMO who met the Berlin definition. The epidemiology and risk factors for barotrauma during ECMO were analyzed. RESULTS: Among 127 patients with ARDS treated with ECMO, barotrauma occurred in 24 (18.9%) during ECMO and 9 (7.1%) after ECMO decannulation, mainly in the late stage of ARDS (75%) and ≥8 days during ECMO (54.2%). Univariate and multivariate analyses showed that younger ARDS patients (OR = 0.953, 95%CI 0.923-0.983, p = 0.003) and those with pneumocystis jirovecii pneumonia (PJP) (OR = 3.15, 95%CI 1.070-9.271, p = 0.037), elevated body temperature after establishing ECMO (OR = 2.997, 95%CI 1.325-6.779, p = 0.008) and low platelet count after establishing ECMO (OR = 0.985, 95%CI 0.972-0.998, p = 0.02) had an increased risk of barotrauma during ECMO. There was no difference in ventilator parameters between patients with and without barotrauma. Barotrauma during ECMO was mainly related to the etiology of the disease and disease state. CONCLUSION: There is a high incidence of barotrauma in ARDS patients during ECMO, even after ECMO decannulation. Young age, PJP, elevated body temperature and low platelet count after establishing ECMO are risk factors of barotrauma, and those patients should be closely monitored by imaging, especially in the late stage of ARDS.