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.

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.

Long-Term Ozone Exposure and Small Airway Dysfunction: The China Pulmonary Health (CPH) Study.

Rationale: It remains unknown whether long-term ozone exposure can impair lung function. Objectives: To investigate the associations between long-term ozone exposure and adult lung function in China. Methods: Lung function results and diagnosis of small airway dysfunction (SAD) were collected from a cross-sectional study, the China Pulmonary Health Study (N = 50,991). We used multivariable linear and logistic regression models to examine the associations of long-term ozone exposure with lung function parameters and SAD, respectively, adjusting for demographic characteristics, individual risk factors, and longitudinal trends. We then performed a stratification analysis by chronic obstructive pulmonary disease (COPD). Measurements and Main Results: We observed that each 1 SD (4.9 ppb) increase in warm-season ozone concentrations was associated with a 14.2 ml/s (95% confidence interval [CI], 8.8-19.6 ml/s] decrease in forced expiratory flow at the 75th percentile of vital capacity and a 29.5 ml/s (95% CI, 19.6-39.5 ml/s) decrease in mean forced expiratory flow between the 25th and 75th percentile of vital capacity. The odds ratio of SAD was 1.09 (95% CI, 1.06-1.11) for a 1 SD increase in warm-season ozone concentrations. Meanwhile, we observed a significant association with decreased FEV1/FVC but not with FEV1 or FVC. The association estimates were greater in the COPD group than in the non-COPD group. Conclusions: We found independent associations of long-term ozone exposure with impaired small airway function and higher SAD risks, while the associations with airflow obstruction were weak. Patients with COPD appear to be more vulnerable.

Physicians' knowledge of invasive fungal disease in China.

BACKGROUND: Invasive fungal disease (IFD) is associated with high morbidity and mortality. Data are lacking regarding physicians' perspectives on the diagnosis and management of IFD in China. OBJECTIVES: To evaluate physicians' perspectives on the diagnosis and management of IFD. METHODS: Based on current guidelines, a questionnaire was designed and administered to 294 physicians working in haematology departments, intensive care units, respiratory departments and infectious diseases departments in 18 hospitals in China. RESULTS: The total score and subsection scores for invasive candidiasis, invasive aspergillosis (IA), cryptococcosis and invasive mucormycosis (IM) were 72.0 ± 12.2 (maximum = 100), 11.1 ± 2.7 (maximum = 19), 43.0 ± 7.8 (maximum = 57), 8.1 ± 2.0 (maximum = 11) and 9.8 ± 2.3 (maximum = 13), respectively. Although the perspectives of the Chinese physicians were in good overall agreement with guideline recommendations, some knowledge gaps were identified. Specific areas in which the physicians' perspectives and guideline recommendations differed included use of the ß-D-glucan test to facilitate the diagnosis of IFD, relative utility of the serum galactomannan test and bronchoalveolar lavage fluid galactomannan test in patients with agranulocytosis, use of imaging in the diagnosis of mucormycosis, risk factors for mucormycosis, indications for initiating antifungal therapy in patients with haematological malignancies, when to start empirical therapy in mechanically ventilated patients, first-line drugs for mucormycosis and treatment courses for IA and IM. CONCLUSION: This study highlights the main areas that could be targeted by training programs to improve the knowledge of physicians treating patients with IFD in China.

IL35 attenuated LPS-induced acute lung injury by regulating macrophage polarization.

BACKGROUND: Interleukin 35 (IL35) has been reported to play a role in acute lung injury (ALI); however, the current results regarding the relationship between IL35 and ALI are inconsistent. Therefore, we aimed to further determine the function of IL35 in ALI in mice and the potential mechanism in this paper. MATERIALS AND METHODS: Hematoxylin-eosin (HE) staining and Masson staining were used to evaluate lung injury in mice. Immunohistochemical staining was used to evaluate the expression of IL35 p35, TLR4 and MD2 and the Bax/Bcl2 and p-P65/P65 ratios. The expression levels of IL35 EBi3, CD68, CD206 and MPO were assessed by immunofluorescence staining. RT-PCR was used to examine the expression levels of IL1ß and IL6. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was performed to detect apoptotic cells. RESULTS: Overexpression of IL35 alleviated LPS-induced ALI in mice. IL35 overexpression decreased the expression of CD68 and increased the expression of CD206 in mice with ALI. Furthermore, upregulation of IL35 expression obviously reduced the expression of MPO, IL1ß and IL6 in the lung tissues of mice with ALI. Mechanistically, IL35 suppressed the TLR4/NFκB-P65 pathway, leading to the promotion of the M1 to M2 macrophage transition and alleviation of inflammation in mice with ALI. CONCLUSIONS: IL35 relieved LPS-induced inflammation and ALI in mice by regulating M1/M2 macrophage polarization and inhibiting the activation of the TLR4/NFκB-P65 pathway.

High-flow nasal cannula versus conventional oxygen therapy in acute COPD exacerbation with mild hypercapnia: a multicenter randomized controlled trial.

BACKGROUND: High-flow nasal cannula (HFNC) can improve ventilatory function in patients with acute COPD exacerbation. However, its effect on clinical outcomes remains uncertain. METHODS: This randomized controlled trial was conducted from July 2017 to December 2020 in 16 tertiary hospitals in China. Patients with acute COPD exacerbation with mild hypercapnia (pH ≥ 7.35 and arterial partial pressure of carbon dioxide > 45 mmHg) were randomly assigned to either HFNC or conventional oxygen therapy. The primary outcome was the proportion of patients who met the criteria for intubation during hospitalization. Secondary outcomes included treatment failure (intolerance and need for non-invasive or invasive ventilation), length of hospital stay, hospital cost, mortality, and readmission at day 90. RESULTS: Among 337 randomized patients (median age, 70.0 years; 280 men [83.1%]; median pH 7.399; arterial partial pressure of carbon dioxide 51 mmHg), 330 completed the trial. 4/158 patients on HFNC and 1/172 patient on conventional oxygen therapy met the criteria for intubation (P = 0.198). Patients progressed to NPPV in both groups were comparable (15 [9.5%] in the HFNC group vs. 22 [12.8%] in the conventional oxygen therapy group; P = 0.343). Compared with conventional oxygen therapy, HFNC yielded a significantly longer median length of hospital stay (9.0 [interquartile range, 7.0-13.0] vs. 8.0 [interquartile range, 7.0-11.0] days) and a higher median hospital cost (approximately $2298 [interquartile range, $1613-$3782] vs. $2005 [interquartile range, $1439-$2968]). There were no significant differences in other secondary outcomes between groups. CONCLUSIONS: In this multi-center randomized controlled study, HFNC compared to conventional oxygen therapy did not reduce need for intubation among acute COPD exacerbation patients with mild hypercapnia. The future studies should focus on patients with acute COPD exacerbation with respiratory acidosis (pH < 7.35). However, because the primary outcome rate was well below expected, the study was underpowered to show a meaningful difference between the two treatment groups. TRIAL REGISTRATION: NCT03003559 . Registered on December 28, 2016.

Associations of residential greenness with lung function and chronic obstructive pulmonary disease in China.

BACKGROUND: Studies on the association of greenness with respiratory health are scarce in developing countries, and previous studies in China have focused on only one or two indicators of lung function. OBJECTIVE: The study aims to evaluate the associations of residential greenness with full-spectrum lung function indicators and prevalence of chronic obstructive pulmonary disease (COPD). METHODS: This nationwide cross-sectional survey included 50,991 participants from the China Pulmonary Health study. Lung function indicators included four categories: indicators of obstructive ventilatory dysfunction (FEV1, FVC and FEV1/FVC); an indicator of large-airway dysfunction (PEF); indicators of small-airway dysfunction (FEF25-75% and FEV3/FEV6); and other indicators. Residential greenness was assessed by the Normalized Difference Vegetation Index (NDVI). Multivariable linear regression models and logistic regression models were used to analyze associations of greenness with lung function and COPD prevalence. RESULTS: Within the 500 m buffer, an interquartile range (IQR) increase in NDVI was associated with higher FEV1 (24.76 mL), FVC (16.52 mL), FEV1/FVC (0.38), FEF50% (56.34 mL/s), FEF75% (33.43 mL/s), FEF25-75% (60.73 mL/s), FEV3 (18.59 mL), and FEV6 (21.85 mL). However, NDVI was associated with lower PEF. In addition, NDVI was significantly associated with 10% lower odds of COPD. The stratified analyses found that the associations were only significant in middle-young people, females, and nonsmokers. The associations were influenced by geographic regions. CONCLUSIONS: Residential greenness was associated with better lung function and lower odds of COPD in China. These findings provide a scientific basis for healthy community planning.

Effect of prone position in patients with acute respiratory distress syndrome supported by venovenous extracorporeal membrane oxygenation: a retrospective cohort study.

BACKGROUND: The application of prone position (PP) in acute respiratory distress syndrome (ARDS) supported by venovenous extracorporeal membrane oxygenation (VV-ECMO) is controversial. OBJECTIVES: To evaluate the safety and efficacy of application of PP during VV-ECMO in patients with ARDS. METHODS: This was a single-center, retrospective study of patients who met the Berlin definition of ARDS, and were supported with VV-ECMO. We divided the patients into two groups. The prone group included patients who were supported by VV-ECMO, and experienced at least one period of PP, while those without PP during VV-ECMO were defined as the supine group. Propensity score matching (PSM) at a ratio of 1:1 was introduced to minimize potential confounders. The primary outcomes were the complications of PP and the change of arterial oxygen pressure/fraction of the inspiration (PaO2/FiO2) ratio after PP. The secondary outcomes were hospital survival, ICU survival, and ECMO weaning rate. RESULTS: From April 2013 to October 2020, a total of 91 patients met the diagnostic criteria of ARDS who were supported with ECMO. 38 patients (41.8%) received at least one period of PP during ECMO, while 53 patients (58.2%) were maintained in supine position during ECMO. 22 minor complications were reported in the prone group and major complications were not found. The other ECMO-related complications were similar between two groups. The PaO2/FiO2 ratio significantly improved after PP compared with before (174.50 (132.40-228.25) mmHg vs. 158.00 (122.93-210.33) mmHg, p < 0.001). PSM selected 25 pairs of patients with similar characteristics. Hospital survival or ICU survival did not differ between the two groups (40% vs. 28%, p = 0.370; 40% vs. 32%, p = 0.556). Significant difference of ECMO weaning rate between two groups was not found (56% vs. 32%, p = 0.087). CONCLUSIONS: PP during VV-ECMO was safe and could improve oxygenation. A large-scale and well-designed RCT is needed in the future.

Risk factors for bloodstream infection (BSI) in patients with severe acute respiratory distress syndrome (ARDS) supported by veno-venous extracorporeal membrane oxygenation (VV-ECMO).

BACKGROUND: There were relatively few studies about the incidence and risk factors for bloodstream infection (BSI) in patients with severe acute respiratory distress syndrome (ARDS) supported by veno-venous extracorporeal membrane oxygenation (VV-ECMO). METHODS: Patients who were diagnosed with severe ARDS and received VV-ECMO treatment in the medical intensive care unit of China-Japan Friendship Hospital from August 2013 to March 2019 were retrospectively studied. The pathogens isolated from blood culture (BC) were identified and analyzed for drug sensitivity. The risk factors for BSI were analyzed by logistic regression. RESULTS: A total of 105 patients were included in this single-center retrospective cohort study. Among them, 23 patients (22%) had BSIs. 19 cases were identified as primary BSI; while the other 4 cases were as secondary BSI. A total of 23 pathogenic strains were isolated from BCs, including gram-negative (G-) bacilli in 21 (91%) cases, gram-positive (G+) cocci in 1 case, fungus in 1 case, and multidrug-resistant (MDR) organisms in 8 cases. Compared with patients without BSI, patients with BSI had a higher Murray score (odds ratio = 6.29, P = 0.01) and more blood transfusion (odds ratio = 1.27, P = 0.03) during ECMO. CONCLUSIONS: The incidence of BSI in patients with severe ARDS supported by VV-ECMO was 22%. G- bacilli was the main pathogen, and most of them were MDR-G- bacilli (MDR-GNB). Higher Murray score and more blood transfusion may be the independent risk factors for BSI.

Transbronchial lung biopsy versus transbronchial lung cryobiopsy in critically ill patients with undiagnosed acute hypoxemic respiratory failure: a comparative study.

BACKGROUND: In patients with acute hypoxemic respiratory failure whose diagnosis is not established after initial evaluation, obtaining a histopathological diagnosis may improve the patients' prognosis. This study aims to compare the safety profile and diagnostic yields between transbronchial lung biopsy (TBLB) and transbronchial lung cryobiopsy (TBLC) in these patients. METHODS: A retrospective comparative study was conducted in a 26-bed intensive care unit over a 5-year period. The consecutive patients with acute hypoxemic respiratory failure who underwent TBLB or TBLC were included to determine the potential etiology. Patients characteristics, procedure related complications, pathological and multidisciplinary discussion (MDD) diagnostic yields, treatment modification and 28-day survival were analyzed. Prognostic factors were identified by Cox regression analysis. RESULTS: Forty-five and 25 consecutive patients underwent TBLB and TBLC, respectively. The patients underwent TBLC were more critical. There was no significant difference in overall procedure related complications of patients underwent TBLB and TBLC [15.6% (7/45) vs 28.0% (7/25), p = 0.212]. The rate of pathological diagnostic yield [72.0% (18/25) vs 37.8% (17/45), p = 0.006], MDD diagnostic yield [84.0% (21/25) vs 55.6% (25/45), p = 0.016] and subsequent treatment modification [84.0% (21/25) vs 57.8% (26/45), p = 0.025] in patients underwent TBLC were significantly higher than those in patients underwent TBLB. Multivariate analysis revealed that MDD diagnosis [HR 0.193 (95% CI 0.047-0.792), p = 0.022] and treatment modification [HR 0.204 (95% CI 0.065-0.638), p = 0.006] may be prognostic protective factors. CONCLUSIONS: TBLC can lead to an increased chance of establishing a diagnosis, which could significantly improve the patients' prognosis, with an acceptable safety profile.

The population pharmacokinetics and dose optimization of polymyxin B in critically ill patients with or without extracorporeal membrane oxygenation.

WHAT IS KNOWN AND OBJECTIVE: The presence of extracorporeal membrane oxygenation (ECMO) is suggested to further exacerbate the pharmacokinetics (PK) alterations that occur during critical illness. The objectives of this study were to determine the population PK model of polymyxin B in critically ill patients with or without ECMO support investigated the influence of ECMO on PK variability and to identify an optimal dosing strategy. METHODS: Forty-four critically ill patients were enrolled, including eight patients with ECMO support. Eight serial serum samples were collected from each patient at steady state. The population PK was determined using NONMEM and Monte Carlo simulation was performed to evaluate the exposures of different dosing regimens. RESULTS: The PK analyses included 342 steady-state concentrations and a two-compartment model was optimal for polymyxin B PK data modelling. In the final model, creatinine clearance (CLCR ) was the significant covariate on CL (typical value 1.27 L/h; between-subject variability 15.1%) and ECMO did not show a significant impact on the polymyxin B PK. Additionally, we found that the PK parameter estimates of patients with and without ECMO support were mostly similar. Based on Monte Carlo simulations, the dose escalation of polymyxin B in patients with increased CLCR improved the probability of achieving required exposure. For patients with CLCR ≤ 120 ml/min, a dosage regimen of 100 mg every 12 h may represent the optimal regimen at an MIC of 1 mg/L. WHAT IS NEW AND CONCLUSION: The impact of ECMO on the polymyxin B PK is likely to be minimal. Our study showed a potential relationship between CLCR and polymyxin B CL, and the dose of polymyxin B should be adjusted in patients with increased CLCR .

Development and Validation of a Screening Questionnaire of COPD from a Large Epidemiological Study in China.

OBJECTIVE: We aimed to establish an easy-to-use screening questionnaire with risk factors and suspected symptoms of COPD for primary health care settings. METHODS: Based on a nationwide epidemiological study of pulmonary health among adults in mainland China (China Pulmonary Health, CPH study) between 2012 and 2015, participants ≥40 years who completed the questionnaire and spirometry tests were recruited and randomly divided into development set and validation set by the ratio of 2:1. Parameters including sex, age, BMI, residence, education, smoking status, smoking pack-years, biomass exposure, parental history of respiratory diseases and daily respiratory symptoms were initially selected for the development of scoring system. Receiver operating characteristic (ROC) curve, area under curve (AUC), positive and negative predictive values were calculated in development set and validation set. RESULTS: After random split by 2:1 ratio, 22443 individuals were assigned to development set and 11221 to validation set. Ten variables were significantly associated with COPD independently in development set after a stepwise selection by multivariable logistic model and used to develop scoring system. The scoring system yielded good discrimination, as measured by AUC of 0.7737, and in the validation set, the AUC was 0.7711. When applying a cutoff point of ≥16, the sensitivity in development set was 0.69 (0.67 - 0.71); specificity 0.72 (0.71 - 0.73), PPV 0.25 (0.24 - 0.26) and NPV 0.94 (0.94 - 0.95). CONCLUSION: We developed and validated a comprehensive screening questionnaire, COPD-CPHS, with good discrimination. The score system still needs to be validated by large cohort in the future.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2022.2042504 .

Outcomes associated with comorbid diabetes among patients with COPD exacerbation: findings from the ACURE registry.

BACKGROUND: Diabetes is a common comorbidity among patients with exacerbation of chronic obstructive pulmonary disease (AECOPD). Diabetes has been reported to be associated with length of stay (LOS), death, and cost among AECOPD patients. However, most studies are retrospective or have small sample sizes. The association for cost has not been researched using diabetes as a main analytic factor. This study aimed to fill gaps mentioned above, to compare basic characteristics between the diabetic and non-diabetic group, and to detect associations between diabetes and clinical outcomes among patients hospitalized with AECOPD. METHODS: A total of 5334 AECOPD patients, classified into diabetic and non-diabetic group, were included from a prospective multicenter patient registry study. Generalized linear regression and logistic regression were separately used for the association between diabetes and direct hospitalization cost and the association between diabetes and LOS. RESULTS: Generally, diabetic patients had a more severe profile, including being older, more overweight or obese, having more former smokers, more emergency room visits in the past 12 months, and more comorbidities occurrence. Diabetic patients also had worse clinical outcomes, including higher cost and longer LOS. Additionally, the generalized linear regression indicated that the marginal mean cost difference between diabetic and non-diabetic patients was RMB (¥) 775.7. CONCLUSIONS: AECOPD patients with comorbid diabetes had a more severe profile and higher direct hospitalization cost. Diabetes screening and integrated care programs might help reduce the heavy comorbidity and economic burden. Moreover, corticosteroids and metformin could be considered in the treatment of these patients. Trial registration Clinicaltrials.gov with the identifier NCT0265752.

Diagnostic value of galactomannan test in non-immunocompromised critically ill patients with influenza-associated aspergillosis: data from three consecutive influenza seasons.

To explore the diagnostic value of a galactomannan (GM) detection for non-immunocompromised critically ill patients with influenza-associated aspergillosis (IAA). In this retrospective case-control study, we explored the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic (ROC) curve (AUC) of serum and bronchoalveolar lavage fluid (BALF) GM tests by four detection strategies at different detection time points and with different compound modes. In total, 90 patients were evaluated. The AUC values of the second serum GM test, the first and second BALF GM tests, were significantly higher (0.839 (95% CI 0.716 to 0.963), P < 0.01; 0.904 (95% CI 0.820 to 0.988), P < 0.01; 0.827 (95% CI 0.694 to 0.961), P = 0.043) than that of the first serum GM test (0.548 (95% CI 0.377 to 0.718)). We found that at least one positive result on two consecutive serum GM tests (0.719 (95% CI 0.588 to 0.849)) was the best compared with the first positive test (0.419 (95% CI 0.342 to 0.641), P < 0.01) and positives on two consecutive tests (0.636 (95% CI 0.483 to 0.790), P = 0.014). However, there were no differences between those three detection strategies of BALF GM. The BALF GM test might have a better diagnostic value for IAA in the ICU than the serum GM test. A possible cutoff value of 1.0 to 1.3 was set for GM from BALF specimens for IAA. A single serum GM test is not routinely recommended, but at least one positive result on two consecutive tests appeared to be useful.

Acute fibrinous and organizing pneumonia complicated with hemophagocytic lymphohistiocytosis caused by chronic active Epstein-Barr virus infection: a case report.

BACKGROUND: Acute fibrinous and organizing pneumonia (AFOP) is a rare lung condition that is associated with acute lung injury. Its etiology may be idiopathic or secondary to a series of conditions, including immune-related diseases, unclassified connective tissue diseases, hematopoietic stem cell transplantation, infections, hematological diseases and drug induced lung toxicity. We report for the first time a case of AFOP complicated with hemophagocytic lymphohistiocytosis (HLH) caused by chronic active Epstein-Barr virus (CAEBV) infection. CASE PRESENTATION: A 64-year-old man was admitted with a complaint of fever and dyspnea for 2 weeks. The patient presented with elevated serum aminotransferase levels, splenomegaly, progressive decrease of red blood cells and platelets, hyperferritinemia, hypofibrinogenemia, and elevated of Soluble interleukin-2 receptor (sCD25). His chest computed tomography (CT) scan revealed multiple patchy consolidation in both lungs and multiple lymphadenopathy in the mediastinum and hilum. The serology for antibodies of VCA-IgG was positive, EBV-DNA in peripheral blood was elevated, and EBV nucleic acid was detected in the alveolar lavage fluid. Histopathology of the lung tissue showed a dominant of intra-alveolar fibrin and organizing pneumonia. Hemophagocytic cells was found in the bone marrow smear and biopsy. EBV-DNA was detected in lung tissue and bone marrow using in situ hybridization with an EBV-encoded RNA (EBER) probe. After 50 days of hospitalization, he was improved in lung and hemogram. CONCLUSION: We report a case of AFOP with HLH caused by CAEBV in an immunocompetent adult, suggesting that AFOP may be a rare but serious complication caused by CAEBV, and glucocorticoid therapy may improve short-term prognosis.

TMT-Based proteomics analysis of LPS-induced acute lung injury.

PURPOSE: The proteome during lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice is unclear. MATERIALS AND METHODS: In this study, eight-week-old male C57BL/6 mice were intraperitoneally injected with LPS and sacrificed 18 hours after LPS administration to identify protein expression levels in lung tissue using tandem mass tag (TMT) analysis for relative quantification. Hematoxylin-eosin (HE) staining was used to evaluate lung injury in mice. Immunohistochemical staining was used to calculate the production of myeloperoxidase (MPO) and TUNEL staining was performed to detect apoptosis. GO functional clustering and KEGG pathway enrichment analyses were performed to determine functions of differentially expressed proteins (DEPs) and transduction pathways. Domain annotation and subcellular localization analysis of the DEPs were also performed. Furthermore, parallel reaction monitoring (PRM) analysis was used to verify the top 30 DEPs. RESULTS: A total of 5188 proteins were found to be expressed in lung tissues from LPS- and saline-treated mice. Among these proteins, 293 were differentially expressed between the two groups; 255 proteins were upregulated in the LPS-treated ALI mice, while 38 were downregulated. GO analysis showed that the DEPs are mainly extracellular, and KEGG analysis suggested that the DEPs are mainly enriched in the NOD-like receptor signaling pathway, complement and coagulation cascades and natural killer cell-mediated cytotoxicity. Enrichment of the DEPs is mainly peptidase S1A, serine proteases, peptidase S1, and the serpin domain. 26.6% of the DEPs are in the nucleus, 24.6% are in the cytosol, 19.1% are in the extracellular space, and 18.8% are in the plasma membrane. PRM validation showed that the trend of 30 DEPs was same with TMT analysis. Among these, Cytochrome b-245 heavy chain (Cybb), Monocyte differentiation antigen CD14 (Cd14) and Neutrophil gelatinase-associated lipocalin (NGAL) were the most obvious change. CONCLUSIONS: Our results may help to identify markers and therapeutic targets for LPS-induced ALI.

Estimation of the area under concentration-time curve of polymyxin B based on limited sampling concentrations in Chinese patients with severe pneumonia.

AIMS: The efficacy and toxicity of polymyxin B (PB) are closely related to its pharmacokinetic/pharmacodynamic (PK/PD) index area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratio. The purpose of this study was to obtain PK data for PB in Chinese severe pneumonia patients and establish appropriate blood sampling time points for the PB therapeutic drug monitoring (TDM). SUBJECT AND METHOD: After treatment with at least four doses of PB (50 IU, q12h), the blood samples were collected immediately after the end of infusion (C0) and 1.5, 2, 4, 6, 8, and 12 h (C1.5, C2, C4, C6, C8, C12) after PB administration. The PB blood plasma concentrations were determined using an ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). All 42 patients were randomly divided into modeling (n = 24) and validation (n = 18) groups. The relationship between AUCss,24h and PB plasma concentration at each time point in modeling group was analyzed using limited sampling strategy and a PK method based on one-compartment with correction model. RESULTS: C6 scheme was found to provide the most accurate prediction of AUCss,24h values (r2 = 0.984) with the target value of 1.9-4.2 µg/ml at steady state to reach the 50-100 µg h/ml criteria of AUCss,24h. C0 with target value of 1.0-2.8 µg/ml can be considered an alternative sampling scheme (r2 = 0.900) but prediction deviation may exist. C0 and Cmax sampling scheme also demonstrated good predicting ability of AUC values using PK model. CONCLUSION: This study provides a clear plan for the implementation of TDM of PB, which is useful for optimizing the dosing regimen and individualizing treatment in severe pneumonia patients.

Circulating Rather Than Alveolar Extracellular Deoxyribonucleic Acid Levels Predict Outcomes in Influenza.

BACKGROUND: High levels of circulating neutrophil extracellular traps (NETs) are associated with a poor prognosis in influenza A infection. It remains unclear whether NETs in the plasma or bronchoalveolar lavage fluid (BALF) can predict clinical outcomes in influenza. METHODS: One hundred eighteen patients who were diagnosed with H1N1 influenza in 2017-2018 were recruited. The NETs were assessed in plasma and BALF samples by quantifying cell-free deoxyribonucleic acid (cfDNA) and protein-DNA complexes. Predictions of severe illness and 60-day mortality were analyzed with receiver operating characteristic curves. RESULTS: The NET levels were significantly elevated in the BALF and contributed to the pathology of lungs, yet it was not associated with disease severity or mortality in patients severely infected with H1N1. Plasma NET levels were significantly increased in the patients with severe influenza and positively correlated with the oxygen index and sequential organ failure assessment scores. High levels of plasma cfDNA (>286.6 ng/mL) or histone-bound DNA (>9.4 ng/mL) discriminated severe influenza from mild, and even higher levels of cfDNA (>306.3 ng/mL) or histone-bound DNA (>23.1 ng/mL) predicted fatal outcomes in severely ill patients. CONCLUSIONS: The cfDNA and histone-bound DNA in plasma represent early predictive biomarkers for the prognosis of influenza.

Co-infection with SARS-CoV-2 and Influenza A Virus in Patient with Pneumonia, China.

We report co-infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus in a patient with pneumonia in China. The case highlights possible co-detection of known respiratory viruses. We noted low sensitivity of upper respiratory specimens for SARS-CoV-2, which could further complicate recognition of the full extent of disease.