Respiratory Research最新文献

Background: Ventilation management may differ between COVID-19 ARDS (COVID-ARDS) patients and patients with pre-COVID ARDS (CLASSIC-ARDS); it is uncertain whether associations of ventilation management with outcomes for CLASSIC-ARDS also exist in COVID-ARDS.

Methods: Individual patient data analysis of COVID-ARDS and CLASSIC-ARDS patients in six observational studies of ventilation, four in the COVID-19 pandemic and two pre-pandemic. Descriptive statistics were used to compare epidemiology and ventilation characteristics. The primary endpoint were key ventilation parameters; other outcomes included mortality and ventilator-free days and alive (VFD-60) at day 60.

Results: This analysis included 6702 COVID-ARDS patients and 1415 CLASSIC-ARDS patients. COVID-ARDS patients received lower median V_T (6.6 [6.0 to 7.4] vs 7.3 [6.4 to 8.5] ml/kg PBW; p < 0.001) and higher median PEEP (12.0 [10.0 to 14.0] vs 8.0 [6.0 to 10.0] cm H₂O; p < 0.001), at lower median ΔP (13.0 [10.0 to 15.0] vs 16.0 [IQR 12.0 to 20.0] cm H₂O; p < 0.001) and higher median Crs (33.5 [26.6 to 42.1] vs 28.1 [21.6 to 38.4] mL/cm H₂O; p < 0.001). Following multivariable adjustment, higher ΔP had an independent association with higher 60-day mortality and less VFD-60 in both groups. Higher PEEP had an association with less VFD-60, but only in COVID-ARDS patients.

Conclusions: Our findings show important differences in key ventilation parameters and associations thereof with outcomes between COVID-ARDS and CLASSIC-ARDS.

Trial registration: Clinicaltrials.gov (identifier NCT05650957), December 14, 2022.

Background: The genetic signatures associated with the susceptibility to nontuberculous mycobacterial pulmonary disease (NTM-PD) are still unknown. In this study, we performed RNA sequencing to explore gene expression profiles and represent characteristic factor in NTM-PD.

Methods: Peripheral blood samples were collected from patients with NTM-PD and healthy individuals (controls). Differentially expressed genes (DEGs) were identified by RNA sequencing and subjected to functional enrichment and immune cell deconvolution analyses.

Results: We enrolled 48 participants, including 26 patients with NTM-PD (median age, 58.0 years; 84.6% female), and 22 healthy controls (median age, 58.5 years; 90.9% female). We identified 21 upregulated and 44 downregulated DEGs in the NTM-PD group compared to those in the control group. NTM infection did not have a significant impact on gene expression in the NTM-PD group compared to the control group, and there were no differences in the proportion of immune cells. However, through gene ontology (GO), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) analysis, we discovered that PARK2 is a key factor associated with NTM-PD. The PARK2 gene, which is linked to the ubiquitination pathway, was downregulated in the NTM-PD group (fold change, - 1.314, P = 0.047). The expression levels of PARK2 remained unaltered after favorable treatment outcomes, suggesting that the gene is associated with host susceptibility rather than with the outcomes of infection or inflammation. The area under the receiver operating characteristic curve for the PARK2 gene diagnosing NTM-PD was 0.813 (95% confidence interval, 0.694-0.932).

Conclusion: We identified the genetic signatures associated with NTM-PD in a cohort of Korean patients. The PARK2 gene presents as a potential susceptibility factor in NTM-PD .

Background: Airflow obstruction is a hallmark of disease severity and prognosis in bronchiectasis. The relationship between lung microbiota, airway inflammation, and outcomes in bronchiectasis with fixed airflow obstruction (FAO) remains unclear. This study explores these interactions in bronchiectasis patients, with and without FAO, and compares them to those diagnosed with chronic obstructive pulmonary disease (COPD).

Methods: This prospective observational study in Taiwan enrolled patients with either bronchiectasis or COPD. To analyze the lung microbiome and assess inflammatory markers, bronchoalveolar lavage (BAL) samples were collected for 16S rRNA gene sequencing. The study cohort comprised 181 patients: 86 with COPD, 46 with bronchiectasis, and 49 with bronchiectasis and FAO, as confirmed by spirometry.

Results: Patients with bronchiectasis, with or without FAO, had similar microbiome profiles characterized by reduced alpha diversity and a predominance of Proteobacteria, distinctly different from COPD patients who exhibited more Firmicutes, greater diversity, and more commensal taxa. Furthermore, compared to COPD and bronchiectasis without FAO, bronchiectasis with FAO showed more severe disease and a higher risk of exacerbations. A significant correlation was found between the presence of Pseudomonas aeruginosa and increased airway neutrophilic inflammation such as Interleukin [IL]-1β, IL-8, and tumor necrosis factor-alpha [TNF]-α, as well as with higher bronchiectasis severity, which might contribute to an increased risk of exacerbations. Moreover, in bronchiectasis patients with FAO, the ROSE (Radiology, Obstruction, Symptoms, and Exposure) criteria were employed to classify individuals as either ROSE (+) or ROSE (-), based on smoking history. This classification highlighted differences in clinical features, inflammatory profiles, and slight microbiome variations between ROSE (-) and ROSE (+) patients, suggesting diverse endotypes within the bronchiectasis with FAO group.

Conclusion: Bronchiectasis patients with FAO may exhibit two distinct endotypes, as defined by ROSE criteria, characterized by greater disease severity and a lung microbiome more similar to bronchiectasis without FAO than to COPD. The significant correlation between Pseudomonas aeruginosa colonization and increased airway neutrophilic inflammation, as well as disease severity, underscores the clinical relevance of microbial patterns. This finding reinforces the potential role of these patterns in the progression and exacerbations of bronchiectasis with FAO.

Background: Thermal ablation is a minimally invasive treatment for non-small cell lung cancer (NSCLC). Aside from causing an immediate direct tumour cell injury, the effects of thermal ablation on the internal microenvironment are unknown. This study aimed to investigate the effects of thermal ablation on the plasma internal environment in patients with NSCLC.

Methods: 128 plasma samples were collected from 48 NSCLC (pre [LC] and after thermal ablation [LC-T]) patients and 32 healthy controls (HCs). Olink proteomics and metabolomics were utilized to construct an integrated landscape of the cancer-related immune and inflammatory responses after ablation.

Results: Compared with HCs, LC patients exhibited 58 differentially expressed proteins (DEPs) and 479 differentially expressed metabolites (DEMs), which might participate in tumour progression and metastasis. Moreover, 75 DEPs were identified among the HC, LC, and LC-T groups. Forty-eight highly expressed DEPs (eg, programmed death-ligand 1 [PD-L1]) in the LC group were found to be downregulated after thermal ablation. These DEPs had significant impacts on pathways such as angiogenesis, immune checkpoint blockade, and pro-tumour chemotaxis. Metabolites involved in tumour cell survival were associated with these proteins at the expression and functional levels. In contrast, 19 elevated proteins (eg, interleukin [IL]-6) were identified after thermal ablation. These proteins were mainly associated with inflammatory response pathways (NF-κB signalling and tumour necrosis factor signalling) and immune cell activation.

Conclusions: Thermal ablation-induced changes in the host plasma microenvironment contribute to anti-tumour immunity in NSCLC, offering new insights into tumour ablation combined with immunotherapy. Trial registration This study was registered on the Chinese Clinical Trial Registry ( https://www.chictr.org.cn/index.html ). ID: ChiCTR2300076517. Registration Date: 2023-10-11.

Objective: To develop and evaluate the predictive value of a simplified lung ultrasound (LUS) method for forecasting respiratory support in term infants.

Methods: This observational, prospective, diagnostic accuracy study was conducted in a tertiary academic hospital between June and December 2023. A total of 361 neonates underwent LUS examination within 1 h of birth. The proportion of each LUS sign was utilized to predict their respiratory outcomes and compared with the LUS score model. After identifying the best predictive LUS sign, simplified models were created based on different scan regions. The optimal simplified model was selected by comparing its accuracy with both the full model and the LUS score model.

Results: After three days of follow-up, 91 infants required respiratory support, while 270 remained healthy. The proportion of confluent B-lines demonstrated high predictive accuracy for respiratory support, with an area under the curve (AUC) of 89.1% (95% confidence interval [CI]: 84.5-93.7%). The optimal simplified model involved scanning the R/L 1-4 region, yielding an AUC of 87.5% (95% CI: 82.6-92.3%). Both the full model and the optimal simplified model exhibited higher predictive accuracy compared to the LUS score model. The optimal cut-off value for the simplified model was determined to be 15.9%, with a sensitivity of 76.9% and specificity of 91.9%.

Conclusions: The proportion of confluent B-lines in LUS can effectively predict the need for respiratory support in term infants shortly after birth and offers greater reliability than the LUS score model.

Background: Cigar use among adults in the United States has remained relatively stable in the past decade and occupies a growing part of the tobacco marketplace as cigarette use has declined. While studies have established the detrimental respiratory health effects of cigarette use, the effects of cigar use need further characterization. In this study, we evaluate the prospective association between cigar use, with or without cigarettes, and asthma exacerbation.

Methods: We used data from Waves 1-5 (2013-2019) of the Population Assessment of Tobacco and Health Study to run generalized estimating equation models examining the association between time-varying, one-wave-lagged cigarette and cigar use and self-reported asthma exacerbation among US adults (18+). We defined our exposure as non-established (reference), former, exclusive cigarette, exclusive cigar, and dual use. We defined an asthma exacerbation event as a reported asthma attack in the past 12 months necessitating oral or injected steroid medication or asthma symptoms disrupting sleep at least once a week in the past 30 days. We adjusted for age, sex, race and ethnicity, household income, health insurance, established electronic nicotine delivery systems use, cigarette pack-years, secondhand smoke exposure, obesity, and baseline asthma exacerbation.

Results: Exclusive cigarette use (incidence rate ratio (IRR): 1.26, 95% confidence interval (CI): 1.03-1.54) and dual use (IRR: 1.41, 95% CI: 1.08-1.85) were associated with a higher rate of asthma exacerbation compared to non-established use, while former use (IRR: 1.01, 95% CI: 0.80-1.28) and exclusive cigar use (IRR: 0.70, 95% CI: 0.42-1.17) were not.

Conclusion: We found no association between exclusive cigar use and self-reported asthma exacerbation. However, exclusive cigarette use and dual cigarette and cigar use were associated with higher incidence rates of self-reported asthma exacerbation compared to non-established use. Studies should evaluate strategies to improve cigarette and cigar smoking cessation among adults with asthma who continue to smoke.

Background: The gut-lung axis, pivotal for respiratory health, is inadequately explored in pulmonary and critical care medicine (PCCM) inpatients.

Methods: Examining PCCM inpatients from three medical university-affiliated hospitals, we conducted 16S ribosomal RNA sequencing on stool samples (inpatients, n = 374; healthy controls, n = 105). We conducted statistical analyses to examine the gut microbiota composition in PCCM inpatients, comparing it to that of healthy controls. Additionally, we explored the associations between gut microbiota composition and various clinical factors, including age, white blood cell count, neutrophil count, platelet count, albumin level, hemoglobin level, length of hospital stay, and medical costs.

Results: PCCM inpatients exhibited lower gut microbiota diversity than healthy controls. Principal Coordinates Analysis revealed marked overall microbiota structure differences. Four enterotypes, including the exclusive Enterococcaceae enterotype in inpatients, were identified. Although no distinctions were found at the phylum level, 15 bacterial families exhibited varying abundances. Specifically, the inpatient population from PCCM showed a significantly higher abundance of Enterococcaceae, Lactobacillaceae, Erysipelatoclostridiaceae, Clostridiaceae, and Tannerellaceae. Using random forest analyses, we calculated the areas under the receiver operating characteristic curves (AUCs) to be 0.75 (95% CIs 0.69-0.80) for distinguishing healthy individuals from inpatients. The four most abundant genera retained in the classifier were Blautia, Subdoligranulum, Enterococcus, and Klebsiella.

Conclusions: Evidence of gut microbiota dysbiosis in PCCM inpatients underscores the gut-lung axis's significance, promising further avenues in respiratory health research.

Background: Previous research has revealed the potential impact of circadian rhythms on pulmonary diseases; however, the connection between circadian rhythm-associated Thyrotroph Embryonic Factor (TEF) and Pulmonary Arterial Hypertension (PAH) remains unclear. We aim to assess the genetic causal relationship between TEF and PAH by utilizing two sets of genetic instrumental variables (IV) and publicly available Pulmonary Arterial Hypertension Genome-Wide Association Studies (GWAS).

Methods: Total of 23 independent TEF genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. Gain- and loss-of-function experiments were used to demonstrate the role of TEF in PAH.

Results: Our analysis revealed that as TEF levels increased genetically, there was a corresponding increase in the risk of PAH, as evidenced by IVW (OR = 1.233, 95% CI: 1.054-1.441; P = 0.00871) and weighted median (OR = 1.292, 95% CI for OR: 1.064-1.568; P = 0.00964) methods. Additionally, the up-regulation of TEF expression was associated with a significantly higher likelihood of abnormal circadian rhythm (IVW: P = 0.0024733, β = 0.05239). However, we did not observe a significant positive correlation between circadian rhythm and PAH (IVW: P = 0.3454942, β = 1.4980398). In addition, our in vitro experiments demonstrated that TEF is significantly overexpressed in pulmonary artery smooth muscle cells (PASMCs). And overexpression of TEF promotes PASMC viability and migratory capacity, as well as upregulates the levels of inflammatory cytokines.

Conclusion: Our analysis suggests a causal relationship between genetically increased TEF levels and an elevated risk of both PAH and abnormal circadian rhythm. Consequently, higher TEF levels may represent a risk factor for individuals with PAH.

Background: Increasing functional residual capacity (FRC) or tidal volume (V_T) reduces airway resistance and attenuates the response to bronchoconstrictor stimuli in animals and humans. What is unknown is which one of the above mechanisms is more effective in modulating airway caliber and whether their combination yields additive or synergistic effects. To address this question, we investigated the effects of increased FRC and increased V_T in attenuating the bronchoconstriction induced by inhaled methacholine (MCh) in healthy humans.

Methods: Nineteen healthy volunteers were challenged with a single-dose of MCh and forced oscillation was used to measure inspiratory resistance at 5 and 19 Hz (R₅ and R₁₉), their difference (R_5-19), and reactance at 5 Hz (X₅) during spontaneous breathing and during imposed breathing patterns with increased FRC, or V_T, or both. Importantly, in our experimental design we held the product of V_T and breathing frequency (BF), i.e, minute ventilation (V_E) fixed so as to better isolate the effects of changes in V_T alone.

Results: Tripling V_T from baseline FRC significantly attenuated the effects of MCh on R₅, R₁₉, R_5-19 and X₅. Doubling V_T while halving BF had insignificant effects. Increasing FRC by either one or two V_T significantly attenuated the effects of MCh on R_5, R₁₉, R_5-19 and X₅. Increasing both V_T and FRC had additive effects on R₅, R₁₉, R_5-19 and X₅, but the effect of increasing FRC was more consistent than increasing V_T thus suggesting larger bronchodilation. When compared at iso-volume, there were no differences among breathing patterns with the exception of when V_T was three times larger than during spontaneous breathing.

Conclusions: These data show that increasing FRC and V_T can attenuate induced bronchoconstriction in healthy humans by additive effects that are mainly related to an increase of mean operational lung volume. We suggest that static stretching as with increasing FRC is more effective than tidal stretching at constant V_E, possibly through a combination of effects on airway geometry and airway smooth muscle dynamics.

Background: Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI.

Results: Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI.

Conclusions: Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI.