Endothelial Cell-Derived Extracellular Vesicles Promote Aberrant Neutrophil Trafficking and Subsequent Remote Lung Injury.

The development of acute respiratory distress syndrome (ARDS) in sepsis is associated with substantial morbidity and mortality. However, the molecular pathogenesis underlying sepsis-induced ARDS remains elusive. Neutrophil heterogeneity and dysfunction contribute to uncontrolled inflammation in patients with ARDS. A specific subset of neutrophils undergoing reverse transendothelial migration (rTEM), which is characterized by an activated phenotype, is implicated in the systemic dissemination of inflammation. Using single-cell RNA sequencing (scRNA-seq), it identified functionally activated neutrophils exhibiting the rTEM phenotype in the lung of a sepsis mouse model using cecal ligation and puncture. The prevalence of neutrophils with the rTEM phenotype is elevated in the blood of patients with sepsis-associated ARDS and is positively correlated with disease severity. Mechanically, scRNA-seq and proteomic analys revealed that inflamed endothelial cell (EC) released extracellular vesicles (EVs) enriched in karyopherin subunit beta-1 (KPNB1), promoting abluminal-to-luminal neutrophil rTEM. Additionally, EC-derived EVs are elevated and positively correlated with the proportion of rTEM neutrophils in clinical sepsis. Collectively, EC-derived EV is identified as a critical regulator of neutrophil rTEM, providing insights into the contribution of rTEM neutrophils to sepsis-associated lung injury.

A novel extracellular vesicle paradigm for the treatment of COVID-19 induced acute respiratory distress syndrome (ARDS).

Efficacy of mesenchymal stem cells (MSCs) for treatment of acute respiratory distress syndrome (ARDS) suggests bioactive bone marrow MSC extracellular vesicles (BM-MSC EVs) may be effective. A patient with severe COVID-19 associated ARDS who was presumed to expire was treated with a BM-MSC EV preparation (14 doses over two months) as a rescue treatment for refractory COVID ARDS. Near complete reversal of lung inflammation and fibrosis (per computed tomography), near complete restoration of mobility, hospital discharge (3 months) with resumption of normal activities of daily living (one year) and return to work occurred. No adverse events occurred despite repeated dosing of investigational product, highlighting safety of this potential therapy for ARDS.

A Retrospective Comparison of Clinical and Laboratory Aspects of Patients With COVID-19-Related Acute Respiratory Distress Syndrome (ARDS) and Non-COVID-19-Related ARDS.

AIM/OBJECTIVE: This study investigated demographic characteristics, hemodynamic values, respiratory datas, laboratory values ​​such as biochemistry and blood gas, and treatment approaches of coronavirus disease 2019 (COVID-19)-related and non-COVID-19-related acute respiratory distress syndrome (ARDS) patients hospitalized in the intensive care unit (ICU). BACKGROUND: Determining the differences and similarities between COVID-19-related ARDS (CARDS) patients and non-COVID-19-related ARDS (NCARDS) patients will be useful to better understand these two diseases. MATERIALS AND METHODS: A total of 32 NCARDS patients who were followed and treated in the ICU for various reasons between January 2015 and December 2020 and 32 CARDS patients who were followed and treated in the ICU for various reasons between March 2020 and December 2020 were examined retrospectively. Age, gender, comorbidities, Glasgow Coma Scale (GCS), Acute Physiology and Chronic Health Evaluation (APACHE) II Score, blood pressure, heart rate, saturation, laboratory results, arterial blood gas (ABG) values, length of stay in the ICU, intubation, the number of days till the patient was extubated, the treatments applied, admission to the service, and mortality were evaluated. RESULTS: In the comparison between the two groups, the demographic data of the patients, the number of days intubated and extubated, APACHE II scores, and ICU length of stay were not statistically different. Values of positive end-expiratory pressure (PEEP), first hospitalization GCS, first hospitalization hemoglobin (Hgb), albumin at first admission, alanine aminotransferase (ALT) at first admission, and steroid use were found to be significantly different in patients with CARDS (p < 0.001). The median of PEEP values (p = 0.04), first admission GCS values (p = 0.04), first admission Hgb values (p = 0.005), albumin values at the first admission (p = 0.03), ALT values (p = 0.03), and the rate of steroid use (p = 0.001) of CARDS patients were significantly higher than those of NCARDS patients. The median of the first hospitalization heart rate values (p = 0.009), first hospitalization saturation values (p = 0.001), and first admission neutrophil values (p = 0.03) in NCARDS patients were significantly higher than that of CARDS patients. There was no significant difference between the two groups in terms of mortality, sedation use, inotropic support, C-reactive protein (CRP), and procalcitonin values. CONCLUSIONS: CARDS and NCARDS have clinical and laboratory similarities and differences. Therefore, there should be differences in our follow-up and treatment approach to these two disease groups.

Drug repurposing of cyclin-dependent kinase inhibitors for neutrophilic acute respiratory distress syndrome and psoriasis.

BACKGROUND: Neutrophilic inflammation, characterized by dysregulated neutrophil activation, triggers a variety of inflammatory responses such as chemotactic infiltration, oxidative bursts, degranulation, neutrophil extracellular traps (NETs) formation, and delayed turnover. This type of inflammation is pivotal in the pathogenesis of acute respiratory distress syndrome (ARDS) and psoriasis. Despite current treatments, managing neutrophil-associated inflammatory symptoms remains a significant challenge. AIM OF REVIEW: This review emphasizes the role of cyclin-dependent kinases (CDKs) in neutrophil activation and inflammation. It aims to highlight the therapeutic potential of repurposing CDK inhibitors to manage neutrophilic inflammation, particularly in ARDS and psoriasis. Additionally, it discusses the necessary precautions for the clinical application of these inhibitors due to potential off-target effects and the need for dose optimization. KEY SCIENTIFIC CONCEPTS OF REVIEW: CDKs regulate key neutrophilic functions, including chemotactic responses, degranulation, NET formation, and apoptosis. Repurposing CDK inhibitors, originally developed for cancer treatment, shows promise in controlling neutrophilic inflammation. Clinical anticancer drugs, palbociclib and ribociclib, have demonstrated efficacy in treating neutrophilic ARDS and psoriasis by targeting off-label pathways, phosphoinositide 3-kinase (PI3K) and phosphodiesterase 4 (PDE4), respectively. While CDK inhibitors offer promising therapeutic benefits, their clinical repurposing requires careful consideration of off-target effects and dose optimization. Further exploration and clinical trials are necessary to ensure their safety and efficacy in treating inflammatory conditions.

From Cosmetic Surgery to Critical Care: Clinical Mimicry of Acute Respiratory Distress Syndrome Following Gluteal Augmentation Surgery.

Gluteal augmentation surgery, commonly known as the Brazilian Butt Lift (BBL), has become increasingly popular and is offered at numerous surgical centers. Typically performed on an outpatient basis, the procedure takes less than four hours, making it an appealing option for many patients. However, BBL is associated with multiple complications, some of which can be severe, resulting in high mortality rates. Most such post-operative adverse events necessitate urgent transfer to hospitals for optimal care, with post-operative respiratory distress being one such critical sign. Fat embolism syndrome (FES) is a notable complication of BBL. The diagnosis of FES is primarily clinical, supported by imaging studies such as chest X-rays and CT scans. FES often goes underdiagnosed due to the lack of definitive diagnostic criteria and its clinical and radiological similarities to other conditions. Despite its underdiagnosis, FES is reported in approximately 0.06% of patients undergoing BBL. Failure to diagnose it early can lead to complications from empiric treatment of other suspected conditions, potentially worsening the prognosis. Our patient developed respiratory failure within an hour after undergoing BBL. The time to symptom onset and the patient's agitation before the respiratory episode broadened the differential for her condition. This case report highlights the importance of recognizing FES and exploring potential preventive measures, including advancements in surgical techniques and prophylactic strategies.

Effect of Dopamine as a Vascular Endothelial Growth Factor Antagonist on the Development of Acute Lung Injury in Sepsis Patients.

BACKGROUND: Sepsis is a dysregulated host immune response stemming from a systemic inflammatory response to microbial invasion, encompassing bacteria, viruses, and other pathogens. The vascular endothelial growth factor (VEGF) was initially identified for its potent induction of endothelial permeability. Studies have proposed a therapeutic role of dopamine in mitigating VEGF-induced permeability, shedding light on its potential in acute respiratory distress syndrome (ARDS) management. MAIN OBJECTIVE: To determine the effect of dopamine as an inhibitor of VEGF and to prevent the progression of sepsis to acute lung injury (ALI) and ARDS. METHODS: A total of 154 critical care unit patients with a diagnosis of sepsis were randomized into two groups: Group I (control group) and Group II (Study group). Both received standard treatment, as per ICU protocol. In addition, the study group (Group II) received a dopamine infusion of 2 micrograms/kg/min. Baseline routine investigation, procalcitonin, and chest X-ray were done. Day one and day seven blood samples were stored for analysis of VEGF levels. Murray's score and sequential organ failure assessment (SOFA) score (organ dysfunction) were calculated from day one to day seven. RESULTS: VEGF levels on day seven were significantly lower in the study group compared to the control group (p<0.05). The PaO2/FiO2 ratio at day seven was significantly increased in the study group than in the control group, indicating an improvement in oxygenation status in the study group. There was a mean ICU stay of 9.3 days in the study group versus 11.6 days in the control group (p<0.05). The SOFA score showed a significant improvement in the study group from day five onwards, indicating a therapeutic effect of dopamine on organ dysfunction in sepsis. CONCLUSION: Dopamine reduces VEGF and lung injury mediated by increased endothelial permeability.

Synthetic Amphipathic Helical Peptide L-37pA Ameliorates the Development of Acute Respiratory Distress Syndrome (ARDS) and ARDS-Induced Pulmonary Fibrosis in Mice.

In this study, we evaluated the ability of the synthetic amphipathic helical peptide (SAHP), L-37pA, which mediates pathogen recognition and innate immune responses, to treat acute respiratory distress syndrome (ARDS) accompanied by diffuse alveolar damage (DAD) and chronic pulmonary fibrosis (PF). For the modeling of ARDS/DAD, male ICR mice were used. Intrabronchial instillation (IB) of 200 µL of inflammatory agents was performed by an intravenous catheter 20 G into the left lung lobe only, leaving the right lobe unaffected. Intravenous injections (IVs) of L-37pA, dexamethasone (DEX) and physiological saline (saline) were used as therapies for ARDS/DAD. L37pA inhibited the circulating levels of inflammatory cytokines, such as IL-8, TNFα, IL1α, IL4, IL5, IL6, IL9 and IL10, by 75-95%. In all cases, the computed tomography (CT) data indicate that L-37pA reduced lung density faster to -335 ± 23 Hounsfield units (HU) on day 7 than with DEX and saline, to -105 ± 29 HU and -23 ± 11 HU, respectively. The results of functional tests showed that L-37pA treatment 6 h after ARDS/DAD initiation resulted in a more rapid improvement in the physiological respiratory lung by 30-45% functions compared with the comparison drugs. Our data suggest that synthetic amphipathic helical peptide L-37pA blocked a cytokine storm, inhibited acute and chronic pulmonary inflammation, prevented fibrosis development and improved physiological respiratory lung function in the ARDS/DAD mouse model. We concluded that a therapeutic strategy using SAHPs targeting SR-B receptors is a potential novel effective treatment for inflammation-induced ARDS, DAD and lung fibrosis of various etiologies.

Plasma MiR-190 is a potential clinical biomarker for acute respiratory distress syndrome in children and its regulatory role in ARDS cell models by targeting KLF15.

BACKGROUND: The present research aimed to investigate the clinical value of plasma miR-190 in children with acute respiratory distress syndrome (ARDS) and the impact of miR-190 on LPS-induced ARDS cell models. METHODS: The plasma miR-190 levels were measured using real-time quantitative reverse transcription PCR (RT-qPCR). LPS-treated human pulmonary microvascular endothelial cells (HPMECs) were established and then transfected with miR-190 mimic, inhibitor, or miR-negative controls. The levels of inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). The effects of miR-190 on HPMEC proliferation and apoptosis were evaluated by CCK-8 assay and flow cytometry. The regulation of KLF15 by miR-190 was detected by luciferase report assay. RESULTS: The plasma miR-190 expression was increased in ARDS children and it was positively related to the severity and 28 day-survival. Plasma miR-190 could distinguish ARDS children from healthy children. Inhibition of miR-190 increased LPS-induced HPMEC cell proliferation and decreased cell apoptosis and inflammatory cytokines IL-6, IL-1ß, and TNF-α. KLF15 was a direct target of miR-190. CONCLUSION: Increased plasma miR-190 may be a clinical diagnostic and prognostic predictor for ARDS children. Inhibition of miR-190 may improve LPS-induced ARDS by increasing cell proliferation, inhibiting cell apoptosis and inflammatory response by targeting KLF15.

Clinical Profile and Course of Patients with Acute Respiratory Distress Syndrome due to COVID-19 in a Middle-Income Region in Mexico.

Introduction: COVID-19 leads to severe clinical complications that culminate in respiratory failure and acute respiratory distress syndrome (ARDS). Despite reports of some comorbidities that contribute to the development of COVID-19-mediated ARDS, there is great variation in mortality rates among critical COVID-19 patients in the world. To date, no studies have described the incidence and comorbidities associated with ARDS due to COVID-19 in the northeastern region of Mexico. Aim of the study: To describe patients diagnosed with ARDS due to COVID-19 in the northeastern region of Mexico, as well as its variations in comparison with other regions of the country. Material and Methods: We conducted a prospective and observational study in a tertiary care center in Northeastern Mexico. All patients diagnosed with SARS-CoV-2 infection and requiring management in the intensive care unit were included. We developed a database that was updated daily with the patients' demographic information, pre-existing diseases, disease severity, and clinical variables. Results: The incidence of ARDS secondary to COVID-19 in HRAEV was high in comparison with other reports. Diabetes mellitus was the risk factor most associated with COVID-19-mediated ARDS. Conclusion: Based on our findings and those previously reported in the literature, there are differences that we discuss between northeastern and central Mexico, and analyze other areas evaluated around the world.

Longitudinal Assessment of ROX and HACOR Scores to Predict Non-Invasive Ventilation Failure in Patients with SARS-CoV-2 Pneumonia.

Introduction: NIV (Non-invasive ventilation) and HFNC (High Flow nasal cannula) are being used in patients with acute respiratory failure. HACOR score has been exclusively calculated for patients on NIV, on other hand ROX index is being used for patients on HFNC. This is first study where ROX index has been used in patients on NIV to predict failure. Aim of the study: This study investigates the comparative diagnostic performance of HACOR score and ROX index to predict NIV failure. Methods: We performed a retrospective cohort study of non-invasively ventilated COVID-19 patients admitted between 1st April 2020 to 15th June 2021 to ICU of a tertiary care teaching hospital located in Central India. We assessed factors responsible for NIV failure, and whether these scores HACOR/ROX index have discriminative capacity to predict risk of invasive mechanical ventilation. Results: Of the 441 patients included in the current study, 179 (40.5%) recovered, while remaining 262 (59.4%) had NIV failure. On multivariable analysis, ROX index > 4.47 was found protective for NIV-failure (OR 0.15 (95% CI 0.03-0.23; p<0.001). Age > 60 years and SOFA score were other significant independent predictors of NIV-failure. The AUC for prediction of failure rises from 0.84 to 0.94 from day 1 to day 3 for ROX index and from 0.79 to 0.92 for HACOR score in the same period, hence ROX score was non-inferior to HACOR score in current study. DeLong's test for two correlated ROC curves had insignificant difference expect day-1 (D1: 0.03 to 0.08; p=3.191e-05, D2: -0.002 to 0.02; p = 0.2671, D3: -0.003 to 0.04; p= 0.1065). Conclusion: ROX score of 4.47 at day-3 consists of good discriminatory capacity to predict NIV failure. Considering its non-inferiority to HACOR score, the ROX score can be used in patients with acute respiratory failure who are on NIV.

Tranexamic Acid and Pulmonary Complications: A Secondary Analysis of an EAST Multicenter Trial.

BACKGROUND: Anti-inflammatory effects of tranexamic acid (TXA) in reducing trauma endotheliopathy may protect from acute lung injury. Clinical data showing this benefit in trauma patients is lacking. We hypothesized that TXA administration mitigates pulmonary complications in penetrating trauma patients. MATERIALS AND METHODS: This is a post-hoc analysis of a multicenter, prospective, observational study of adults (18+ years) with penetrating torso and/or proximal extremity injury presenting at 25 urban trauma centers. Tranexamic acid administration in the prehospital setting or within three hours of admission was examined. Participants were propensity matched to compare similarly injured patients. The primary outcome was development of pulmonary complication (ARDS and/or pneumonia). RESULTS: A total of 2382 patients were included, and 206 (8.6%) received TXA. Of the 206, 93 (45%) received TXA prehospital and 113 (55%) received it within three hours of hospital admission. Age, sex, and incidence of massive transfusion did not differ. The TXA group was more severely injured, more frequently presented in shock (SBP < 90 mmHg), developed more pulmonary complications, and had lower survival (P < 0.01 for all). After propensity matching, 410 patients remained (205 in each cohort) with no difference in age, sex, or rate of shock. On logistic regression, increased emergency department heart rate was associated with pulmonary complications. Tranexamic acid was not associated with different rate of pulmonary complications or survival on logistic regression. Survival was not different between the groups on logistic regression or propensity score-matched analysis. CONCLUSIONS: Tranexamic acid administration is not protective against pulmonary complications in penetrating trauma patients.

Early predictive values of clinical assessments for ARDS mortality: a machine-learning approach.

Acute respiratory distress syndrome (ARDS) is a devastating critical care syndrome with significant morbidity and mortality. The objective of this study was to evaluate the predictive values of dynamic clinical indices by developing machine-learning (ML) models for early and accurate clinical assessment of the disease prognosis of ARDS. We conducted a retrospective observational study by applying dynamic clinical data collected in the ARDSNet FACTT Trial (n = 1000) to ML-based algorithms for predicting mortality. In order to compare the significance of clinical features dynamically, we further applied the random forest (RF) model to nine selected clinical parameters acquired at baseline and day 3 independently. An RF model trained using clinical data collected at day 3 showed improved performance and prognostication efficacy (area under the curve [AUC]: 0.84, 95% CI: 0.78-0.89) compared to baseline with an AUC value of 0.72 (95% CI: 0.65-0.78). Mean airway pressure (MAP), bicarbonate, age, platelet count, albumin, heart rate, and glucose were the most significant clinical indicators associated with mortality at day 3. Thus, clinical features collected early (day 3) improved performance of integrative ML models with better prognostication for mortality. Among these, MAP represented the most important feature for ARDS patients' early risk stratification.

Longer ICU stay and invasive mechanical ventilation accelerate telomere shortening in COVID-19 patients 1 year after recovery.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes virus-induced-senescence. There is an association between shorter telomere length (TL) in coronavirus disease 2019 (COVID-19) patients and hospitalization, severity, or even death. However, it remains unknown whether virus-induced-senescence is reversible. We aim to evaluate the dynamics of TL in COVID-19 patients 1 year after recovery from intensive care units (ICU). Longitudinal study enrolling 49 patients admitted to ICU due to COVID-19 (August 2020 to April 2021). Relative telomere length (RTL) quantification was carried out in whole blood by monochromatic multiplex real-time quantitative PCR (MMqPCR) assay at hospitalization (baseline) and 1 year after discharge (1-year visit). The association between RTL and ICU length of stay (LOS), invasive mechanical ventilation (IMV), prone position, and pulmonary fibrosis development at 1-year visit was evaluated. The median age was 60 years, 71.4% were males, median ICU-LOS was 12 days, 73.5% required IMV, and 38.8% required a prone position. Patients with longer ICU-LOS or who required IMV showed greater RTL shortening during follow-up. Patients who required pronation had a greater RTL shortening during follow-up. IMV patients who developed pulmonary fibrosis showed greater RTL reduction and shorter RTL at the 1-year visit. Patients with longer ICU-LOS and those who required IMV had a shorter RTL in peripheral blood, as observed 1 year after hospital discharge. Additionally, patients who required IMV and developed pulmonary fibrosis had greater telomere shortening, showing shorter telomeres at the 1-year visit. These patients may be more prone to develop cellular senescence and lung-related complications; therefore, closer monitoring may be needed.

Definition and management of right ventricular injury in adult patients receiving extracorporeal membrane oxygenation for respiratory support using the Delphi method: a PRORVnet study. Expert position statements.

PURPOSE: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is an integral part of the management algorithm of patients with severe respiratory failure refractory to evidence-based conventional treatments. Right ventricular injury (RVI) pertaining to abnormalities in the dimensions and/or function of the right ventricle (RV) in the context of VV-ECMO significantly influences mortality. However, in the absence of a universally accepted RVI definition and evidence-based guidance for the management of RVI in this very high-risk patient cohort, variations in clinical practice continue to exist. METHODS: Following a systematic search of the literature, an international Steering Committee consisting of eight healthcare professionals involved in the management of patients receiving ECMO identified domains and knowledge gaps pertaining to RVI definition and management where the evidence is limited or ambiguous. Using a Delphi process, an international panel of 52 Experts developed Expert position statements in those areas. The process also conferred RV-centric overarching open questions for future research. Consensus was defined as achieved when 70% or more of the Experts agreed or disagreed on a Likert-scale statement or when 80% or more of the Experts agreed on a particular option in multiple-choice questions. RESULTS: The Delphi process was conducted through four rounds and consensus was achieved on 31 (89%) of 35 statements from which 24 Expert position statements were derived. Expert position statements provided recommendations for RVI nomenclature in the setting of VV-ECMO, a multi-modal diagnostic approach to RVI, the timing and parameters of diagnostic echocardiography, and VV-ECMO settings during RVI assessment and management. Consensus was not reached on RV-protective driving pressure thresholds or the effect of prone positioning on patient-centric outcomes. CONCLUSION: The proposed definition of RVI in the context of VV-ECMO needs to be validated through a systematic aggregation of data across studies. Until further evidence emerges, the Expert position statements can guide informed decision-making in the management of these patients.

COVID-19 Related Acute Respiratory Distress Syndrome versus Classical Acute Respiratory Distress Syndrome Patients: Inflammatory Biomarkers as Predictors of Mortality in Pulmonary Septic Shock.

Introduction and Objectives: Coronavirus disease-2019 (COVID-19)-related severe acute respiratory distress syndrome (ARDS) differs pathophysiological from other pulmonary septic shock-related ARDS. Thus, we assessed whether all-cause in-hospital mortality differs for severe COVID-19-related and classical severe ARDS and which inflammatory biomarkers can predict mortality among these patients. Material and Methods: This single-center, retrospective, observational cohort study included pulmonary septic shock patients (n = 114) with COVID-19-related and classical severe ARDS admitted in the Intensive Care Unit. Results: Patients with a mean age of 73 (IQR 62-82), predominantly male (63%), were divided into two groups based on outcomes: survivors (n = 50) and non-survivors (n = 64). COVID-19-related severe ARDS (n = 48) accounts for 75% of deaths. Present comorbidities like heart disease (p = 0.043), neurologic disorders (p = 0.018), and liver disease (p = 0.038) were associated with in-hospital mortality, as well. Regarding inflammatory biomarkers, the AUC/c-statistic was 0.656 (95% CI: 0.53-0.759) for leukocytes, 0.613 (95% CI: 0.509-0.717) C-reactive protein (CRP) and 0.651 (95% CI: 0.548-0.753) for procalcitonin in predicting all-cause in-hospital mortality among patients with pulmonary septic shock and severe ARDS. Conclusion: Patients with pulmonary septic shock and with COVID-19-related severe ARDS had a higher incidence of in-hospital mortality than those with classical severe ARDS. The high value of leukocytes, C-reactive protein, and procalcitonin were predictive for all-cause in-hospital mortality in patients with pulmonary septic shock and ARDS. Infection with COVID-19 was an independent predictor of in-hospital mortality in the presence of ARDS.

The therapeutic potential of gelsolin in attenuating cytokine storm, ARDS, and ALI in severe COVID-19.

Severe COVID-19 cases often progress to life-threatening conditions such as acute respiratory distress syndrome (ARDS), sepsis, and multiple organ dysfunction syndrome (MODS). Gelsolin (GSN), an actin-binding protein with anti-inflammatory and immunomodulatory properties, is a promising therapeutic target for severe COVID-19. Plasma GSN levels are significantly decreased in critical illnesses, including COVID-19, correlating with dysregulated immune responses and poor outcomes. GSN supplementation may mitigate acute lung injury, ARDS, and sepsis, which share pathophysiological features with severe COVID-19, by scavenging actin, modulating cytokine production, enhancing macrophage phagocytosis, and stabilizing the alveolar-capillary barrier. Preliminary data indicate that recombinant human plasma GSN improves oxygenation and lung function in severe COVID-19 patients with ARDS. Although further research is needed to optimize GSN therapy, current evidence supports its potential to mitigate severe consequences of COVID-19 and improve patient outcomes. This review provides a comprehensive analysis of the biological characteristics, mechanisms, and therapeutic value of GSN in severe COVID-19.

Was there a weekend effect on mortality rates for hospitalized patients with COVID-19 and acute myocardial infarction? Insights from the National Inpatient Sample, 2020.

Our study aimed to assess the effect of weekend versus weekday hospital admissions on all-cause mortality in patients with acute myocardial infarction (AMI) and COVID-19 during the COVID-19 pandemic. We analyzed data from the National Inpatient Sample (NIS) 2020, identifying patients with co-existing AMI and COVID-19 admitted on weekdays and weekends. Baseline demographics, comorbidities, and outcomes were assessed. A multivariable regression analysis was conducted, adjusting for confounders to determine the odds of all-cause mortality. Among 74,820 patients, 55,145 (73.7%) were admitted on weekdays, while 19,675 (26.3%) were admitted on weekends. Weekend admissions showed slightly higher proportions of men (61.3% vs. 60%) and whites (56.3% vs. 54.9%) with a median age of 73 years (range: 62-82). The overall all-cause mortality had an odds ratio (OR) of 1.00 (95% CI, 0.92-1.09; P = 0.934). After adjusting for covariates, there was no significant associations between mortality and hospital type (rural: OR = 1.04; 95% CI, 0.78-1.39; P = 0.789; urban teaching: OR = 1.04; 95% CI, 0.94-1.14; P = 0.450) or geographic region (Northeast: OR = 1.16; 95% CI, 0.96-1.39; P = 0.12; Midwest: OR = 0.99; 95% CI, 0.83-1.17; P = 0.871; South: OR = 0.97; 95% CI, 0.85-1.12; P = 0.697; West: OR = 0.94; 95% CI, 0.77-1.15; P = 0.554). There was no significant difference in the rate of all-cause mortality among patients admitted for AMI and COVID-19 between weekdays and weekends.

Clinical characteristics and risk factors for mortality in pneumonia-associated acute respiratory distress syndrome patients: a single center retrospective cohort study.

Background: Pathogenic diversity may have contributed to the high mortality of pneumonia-associated acute respiratory distress syndrome (p-ARDS). Metagenomics next-generation sequencing (mNGS) serves as a valuable diagnostic tool for early pathogen identification. However, its clinical utility in p-ARDS remains understudied. There are still limited researches on the etiology, clinical characteristics and risk factors for 28-day mortality in p-ARDS patients. Methods: A single center retrospective cohort study of 75 p-ARDS patients was conducted. Patients were categorized into survival and deceased groups based on their 28-day outcomes. A comprehensive clinical evaluation was conducted, including baseline characteristics, laboratory indicators, outcomes and pathogen identification by mNGS and traditional microbiological testing. We then evaluated the diagnostic value of mNGS and identified clinical characteristics and risk factors for 28-day mortality in p-ARDS. Result: The overall ICU mortality was 26.67%, and the 28-day mortality was 57.33%, with 32 cases (42.67%) in the survival group, and 43 cases (57.33%) in the deceased group. Patients in the deceased group were older than those in the survival group (68(59,73) years vs. 59(44,67) years, P=0.04). The average lengths of ICU and hospital stay were 9(5,13) days and 14(7,21) days, respectively. The survival group had longer lengths of ICU and hospital stay (ICU: 11(7,17) days and hospital: 17(9,27) days) compared to the deceased group (ICU: 8(4,11) days and hospital: 12(6,19) days) (P<0.05). Survival patients exhibited lower Acute Physiology and Chronic Health Evaluation (APACHE) II score on the 3rd and 7th days, higher lymphocyte counts, higher CD3+ and CD8+ T cell counts compared to deceased patients (P<0.05). Multivariate logistic regression analysis identified age, APACHE II scores on 3rd and 7th days, CD8+ T cell count and length of ICU as independent risk factors for 28-day mortality in p-ARDS patients. mNGS demonstrated a significantly higher overall pathogen detection rate (70/75, 93.33%) compared to the traditional method (50/75, 66.67%, P=0.022). The average turnaround time (TAT) for mNGS was significantly shorter at 1(1,1) day compared to 4(3,5) days for the traditional method (P<0.001). Conclusion: Metagenome next-generation sequencing can be used as a valuable tool for identifying pathogens in p-ARDS, reducing diagnostic time and improving accuracy. Early application of mNGS alongside traditional methods is recommended for p-ARDS. Furthermore, older age, higher APACHE II scores, lower lymphocyte counts and lymphocyte subset counts were associated with increased mortality in p-ARDS patients, highlighting the importance of timely assessment of immune status and disease severity, especially in elderly.

In-hospital mortality, comorbidities, and costs of one million mechanically ventilated patients in Germany: a nationwide observational study before, during, and after the COVID-19 pandemic.

Background: Even more than hospital care in general, intensive care and mechanical ventilation capacities and its utilization in terms of rates, indications, ventilation types and outcomes vary largely among countries. We analyzed complete and nationwide data for Germany, a country with a large intensive care sector, before, during and after the COVID-19 pandemic. Methods: Analysis of administrative claims data, provided by the German health insurance, from all hospitals for all individual patients who were mechanically ventilated between 2019 and 2022. The data included age, sex, diagnoses, length of stay, procedures (e.g., form and duration of mechanical ventilation), outcome (dead vs. alive) and costs. We included all patients who were at least 18 years old at the time of discharge from January 1st, 2019 to December 31st, 2022. Patients were grouped according to year, age group and the form of mechanical ventilation. We further analyzed subgroups of patients being resuscitated and those being COVID-19 positive (vs. negative). Findings: During the four years, 1,003,882 patients were mechanically ventilated in 1395 hospitals. Rates per 100,000 inhabitants varied across age groups from 110 to 123 (18-59 years) to 1101-1275 (>80 years). The top main diagnoses were other forms of heart diseases, pneumonia, chronic obstructive pulmonary disease (COPD), ischemic heart diseases and cerebrovascular diseases. 43.3% (437,031/1,003,882) of all mechanically ventilated patients died in hospital with a remarkable increase in mortality with age and from 2019 to 2022 by almost 5%-points. The in-hospital mortality of ventilated COVID-19 patients was 53.7% (46,553/86,729), while it was 42.6% (390,478/917,153) in non-COVID patients. In-hospital mortality varied from 27.0% in non-invasive mechanical ventilation (NIV) only to 53.4% in invasive mechanical ventilation only cases, 59.4% with early NIV failure, 68.6% with late NIV failure, to 74.0% in patients receiving VV-ECMO and 80.0% in VA-ECMO. 17.5% of mechanically ventilated patients had been resuscitated before, of whom 78.2% (153,762/196,750) died. Total expenditure was around 6 billion Euros per year, i.e. 0.17% of the German GDP. Interpretation: Mechanical ventilation was widely used, before, during and after the COVID-19 pandemic in Germany, reaching more than 1000 patients per 100,000 inhabitants per year in the age over 80 years. In-hospital mortality rates in this nationwide and complete cohort exceeded most of the data known by far. Funding: This research did not receive any dedicated funding.

PD-L1 and PD-1 Are Associated with Clinical Outcomes and Alveolar Immune Cell Activation in ARDS.

The relationship between the Programmed Death-Ligand 1 (PD-L1)/Programmed Death-1 (PD-1) pathway, lung inflammation, and clinical outcomes in acute respiratory distress syndrome (ARDS) is poorly understood. We sought to determine whether PD-L1/PD-1 in the lung or blood is associated with ARDS and associated severity. We measured soluble PD-L1 (sPD-L1) in plasma and lower respiratory tract samples (ARDS1 (n = 59) and ARDS2 (n = 78)) or plasma samples alone (ARDS3 (n = 149)) collected from subjects with ARDS and tested for associations with mortality using multiple regression. We used mass cytometry to measure PD-L1/PD-1 expression and intracellular cytokine staining in cells isolated from bronchoalveolar lavage fluid (BALF) (n = 18) and blood (n = 16) from critically-ill subjects with or without ARDS enrolled from a fourth cohort. Higher plasma levels of sPD-L1 were associated with mortality in ARDS1, ARDS2, and ARDS3. In contrast, higher levels of sPD-L1 in the lung were either not associated with mortality (ARDS2) or were associated with survival (ARDS1). Alveolar PD-1POS T cells had more intracellular cytokine staining compared with PD-1NEG T cells. Subjects without ARDS had a higher ratio of PD-L1POS alveolar macrophages to PD-1POS T cells compared with subjects with ARDS. We conclude that sPD-L1 may have divergent cellular sources and/or functions in the alveolar vs. blood compartments given distinct associations with mortality. Alveolar leukocyte subsets defined by PD-L1/PD-1 cell-surface expression have distinct cytokine secretion profiles, and the relative proportions of these subsets are associated with ARDS.