Influence of vaccination on critical COVID-19 patients with acute respiratory failure: a retrospective cohort study.

BACKGROUND: Despite vaccines' effectiveness in reducing COVID-19 infection rates and disease severity, their impact on critical patients presenting with acute respiratory failure is elusive. The aim of this study was to further investigate the influence of vaccination on mortality rates among severely ill COVID-19 patients experiencing acute respiratory failure. METHODS: This retrospective cohort study was carried out at a tertiary medical center in Taiwan. From April to September 2022, patients who tested positive for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through reverse transcription polymerase chain reaction (RT-PCR) and subsequently experienced acute respiratory failure were included in the study. Baseline characteristics, including vaccination history, along with information regarding critical illness and clinical outcomes, were gathered and compared between patients who received the vaccine and those who did not. RESULTS: A total of 215 patients with COVID-19 exhibiting acute respiratory failure, as confirmed via RT‒PCR, were included in the analysis. Of this cohort, sixty-six (30.7%) patients died within 28 days. Neither administration of the vaccine nor achievement of primary series vaccination status had a significantly different effect on 28 day mortality, number of viral shedding events, acute respiratory distress syndrome (ARDS) incidence or other clinical outcomes. Patients who received the booster vaccine and completed the primary series showed a tendency of increased 28 days of ventilator-free status, though this difference was not statistically significant (p = 0.815). CONCLUSIONS: Vaccination status did not significantly influence mortality rates, the occurrence of ARDS, or the viral shedding duration in COVID-19 patients with acute respiratory failure.

Inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A2AR improves hepatic and cardiac dysfunction of NASH mice.

A2AR-disrupted mice is characterized by severe systemic and visceral adipose tissue (VAT) inflammation. Increasing adenosine cyclase (AC), cAMP, and protein kinase A (PKA) formation through A2AR activation suppress systemic/VAT inflammation in obese mice. This study explores the effects of 4 wk A2AR agonist PSB0777 treatment on the VAT-driven pathogenic signals in hepatic and cardiac dysfunction of nonalcoholic steatohepatitis (NASH) obese mice. Among NASH mice with cardiac dysfunction, simultaneous decrease in the A2AR, AC, cAMP, and PKA levels were observed in VAT, liver, and heart. PSB0777 treatment significantly restores AC, cAMP, PKA, and hormone-sensitive lipase (HSL) levels, decreased SREBP-1/FASN, MCP-1, and CD68 levels, reduces infiltrated CD11b+ F4/80+ cells and adipogenesis in VAT of NASH + PSB0777 mice. The changes in VAT were accompanied by the suppression of hepatic and cardiac lipogenic/inflammatory/injury/apoptotic/fibrotic markers, the normalization of cardiac contractile [sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2)] marker, and cardiac dysfunction. The in vitro approach revealed that conditioned media (CM) of VAT of NASH mice (CMnash) trigger palmitic acid (PA)-like lipotoxic (lipogenic/inflammatory/apoptotic/fibrotic) effects in AML-12 and H9c2 cell systems. Significantly, A2AR agonist pretreatment-related normalization of A2AR-AC-cAMP-PKA levels was associated with the attenuation of CMnash-related upregulation of lipotoxic markers and the normalization of lipolytic (AML-12 cells) or contractile (H9C2 cells) marker/contraction. The in vivo and in vitro experiments revealed that A2AR agonists are potential agent to inhibit the effects of VAT inflammation-driven pathogenic signals on the hepatic and cardiac lipogenesis, inflammation, injury, apoptosis, fibrosis, hypocontractility, and subsequently improve hepatic and cardiac dysfunction in NASH mice.NEW & NOTEWORTHY Protective role of adenosine A2AR receptor (A2AR) and AC-cAMP-PKA signaling against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) possibly via its actions on adipocytes is well known in the past decade. Thus, this study evaluates pharmacological activities of A2AR agonist PSB0777, which has already demonstrated to treat NASH. In this study, the inhibition of visceral adipose tissue-derived pathogenic signals by activation of adenosine A2AR with A2AR agonist PSB0777 improves the hepatic and cardiac dysfunction of high-fat diet (HFD)-induced NASH mice.

Clinical characteristics and outcomes among critically ill patients with cancer and COVID-19-related acute respiratory failure.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has affected individuals worldwide, and patients with cancer are particularly vulnerable to COVID-19-related severe illness, respiratory failure, and mortality. The relationship between COVID-19 and cancer remains a critical concern, and a comprehensive investigation of the factors affecting survival among patients with cancer who develop COVID-19-related respiratory failure is warranted. We aim to compare the characteristics and outcomes of COVID-19-related acute respiratory failure in patients with and without underlying cancer, while analyzing factors affecting in-hospital survival among cancer patients. METHODS: We conducted a retrospective observational study at Taipei Veterans General Hospital in Taiwan from May to September 2022, a period during which the omicron variant of the severe acute respiratory syndrome coronavirus 2 was circulating. Eligible patients had COVID-19 and acute respiratory failure. Clinical data, demographic information, disease severity markers, treatment details, and outcomes were collected and analyzed. RESULTS: Of the 215 enrolled critically ill patients with COVID-19, 65 had cancer. The patients with cancer were younger and had lower absolute lymphocyte counts, higher ferritin and lactate dehydrogenase (LDH) concentrations, and increased vasopressor use compared with those without cancer. The patients with cancer also received more COVID-19 specific treatments but had higher in-hospital mortality rate (61.5% vs 36%, P = 0.002) and longer viral shedding (13 vs 10 days, P = 0.007) than those without cancer did. Smoking [odds ratio (OR): 5.804, 95% confidence interval (CI): 1.847-39.746], elevated LDH (OR: 1.004, 95% CI: 1.001-1.012), vasopressor use (OR: 5.437, 95% CI: 1.202-24.593), and new renal replacement therapy (OR: 3.523, 95% CI: 1.203-61.108) were independent predictors of in-hospital mortality among patients with cancer and respiratory failure. CONCLUSION: Critically ill patients with cancer experiencing COVID-19-related acute respiratory failure present unique clinical features and worse clinical outcomes compared with those without cancer. Smoking, elevated LDH, vasopressor use, and new renal replacement therapy were risk factors for in-hospital mortality in these patients.

Association of Late Radiographic Assessment of Lung Edema Score with Clinical Outcome in Patients with Influenza-Associated Acute Respiratory Distress Syndrome.

Background: Influenza virus infection leads to acute pulmonary injury and acute respiratory distress syndrome (ARDS). The Radiographic Assessment of Lung Edema (RALE) score has been proposed as a reliable tool for the evaluation of the opacity of chest X-rays (CXRs). This study aimed to examine the RALE scores and outcomes in patients with influenza-associated ARDS. Methods: Patients who were newly diagnosed with influenza-associated ARDS from December 2015 to March 2016 were enrolled. Two independent reviewers scored the CXRs obtained on the day of ICU admission and on days 2 and 7 after intensive care unit (ICU) admission. Results: During the study, 47 patients had influenza-associated ARDS. Five died within 7 days of ICU admission. Of the remaining 42, non-survivors (N = 12) had higher Sequential Organ Failure Assessment scores (SOFA) at ICU admission and higher day 7 RALE scores than survivors (N = 30). The day 7 RALE score independently related to late in-hospital mortality (aOR = 1.121, 95% CI: 1.014-1.240, p = 0.025). Conclusions: The RALE score for the evaluation of opacity on CXRs is a highly reproducible tool. Moreover, RALE score on day 7 was an independent predictor of late in-hospital mortality in patients with influenza-associated ARDS.

Analysis of the effect of cytomegalovirus infection in clinical outcomes and prolonged duration of SARS-CoV-2 shedding in intensive care unit patients with COVID-19 pneumonia.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global outbreak disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Cytomegalovirus (CMV) infection can occur in critical COVID-19 patients and is associated with adverse clinical outcomes. OBJECTIVE: The aim of this study was to explore the clinical characteristics and outcome of CMV infection in critical COVID-19 patients. DESIGN: This was a retrospective cohort study. METHODS: From May to September 2021, SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR)-confirmed COVID-19 patients with intensive care unit (ICU) admission were enrolled. CMV infection was confirmed by PCR. Baseline characteristics, critical illness data and clinical outcomes were recorded and analyzed. RESULTS: Seventy-two RT-PCR-confirmed COVID-19 patients with ICU admission were included during the study period and 48 (66.7%) patients required mechanical ventilation (MV). Overall, in-hospital mortality was 19.4%. Twenty-one (29.2%) patients developed CMV infection. Patients with CMV infection had a higher likelihood of diabetes, higher lactate dehydrogenase and lactate levels, and higher proportions of MV, anticoagulant, and steroid use. Patients with CMV infection were associated with longer duration of SARS-CoV-2 shedding, longer ICU and hospital stay, and fewer ventilator-free days. The independent risk factor for development of CMV infection was a higher accumulative steroid dose. CONCLUSION: CMV infection adversely impacted the outcomes of critical COVID-19 patients, resulting in longer ICU stays, longer mechanical ventilation uses and prolonged shedding of SARS-CoV-2.

Comparison of clinical outcomes in critically ill COVID-19 patients on mechanical ventilation with nosocomial pneumonia between Alpha and Omicron variants.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a pandemic that has resulted in millions of deaths worldwide. Critically ill COVID-19 patients who require intubation and develop nosocomial pneumonia, commonly caused by gram-negative bacilli, have a higher mortality rate than those without nosocomial pneumonia. OBJECTIVES: The aim of this study is to compare the clinical characteristics and outcomes and associated risk factors of Alpha and Omicron SARS-CoV-2 variants in critically ill patients on mechanical ventilation (MV) with nosocomial pneumonia. DESIGN: This is a retrospective single-center cohort study. METHODS: This observational study was conducted at Taipei Veterans General Hospital, Taiwan from May 2021 to September 2022. Critically ill patients who had confirmed SARS-CoV-2 infection and intubated on a MV with bacterial pneumonia were enrolled. Demographic data, laboratory results, and treatment information were collected and analyzed. In addition, clinical outcomes among different SARS-CoV-2 variants were examined. RESULTS: This study included 94 critically ill COVID-19 patients who required intubation and intensive care unit (ICU) admission. The Alpha group had a longer duration of SARS-CoV-2 viral shedding, MV days, and ICU stay, while the Omicron group had older age, more comorbidities, higher APACHE II scores, and higher in-hospital mortality (47.0% versus 25.0%, p = 0.047). However, independent risk factors for in-hospital mortality included malignancy, lower serum albumin levels, and lack of Remdesivir treatment, except for the SARS-CoV-2 variant. CONCLUSION: Our study discovered a higher in-hospital mortality rate in severe COVID-19 patients with MV and secondary pneumonia infected with the Omicron variant compared to the Alpha variant; however, real independent risk factors for in-hospital mortality are malignancy, lower serum albumin level, and lack of Remdesivir treatment.

Prediction models combining zonulin, LPS, and LBP predict acute kidney injury and hepatorenal syndrome-acute kidney injury in cirrhotic patients.

The development of acute kidney injury (AKI) and hepatorenal syndrome-acute kidney injury (HRS-AKI) in cirrhosis has been associated with intestinal barrier dysfunction and gut-kidney crosstalk. We use the related markers such as zonulin, lipopolysaccharides (LPS), and lipopolysaccharide-binding protein (LBP) to predict AKI and HRS-AKI in cirrhotic patients and evaluate their in vitro effects on intestinal (Caco-2) cells and renal tubular (HK-2) cells. From 2013 to 2020, we enrolled 70 cirrhotic patients and developed prediction models for AKI and HRS-AKI over a six-month period. There were 13 (18.6%) and 8 (11.4%) cirrhotic patients developed AKI and HRS-AKI. The prediction models incorporated zonulin, LPS, LBP, C-reactive protein, age, and history of hepatitis B for AKI, and zonulin, LPS, LBP, total bilirubin, and Child-Pugh score for HRS-AKI. The area under curve (AUC) for the prediction of AKI and HRS-AKI was 0.94 and 0.95, respectively. Furthermore, the conditioned medium of LPS+hrLBP pre-treated Caco-2 cells induced apoptosis, necrosis, and zonulin release in HK-2 cells, demonstrating the communication between them. This study found that zonulin, LPS, and LBP are potential practical markers for predicting AKI and HRS-AKI in cirrhotic patients, which may serve as potential targets for renal outcomes in cirrhotic patients.

Interstitial lung disease related to occupational hard metal exposure: two case reports.

BACKGROUND: Hard metal lung disease (HMLD) is a relatively less known occupational interstitial lung disease, and instances of HMLD resulting from para-occupational exposure are rarely reported. CASE PRESENTATION: This paper presents two cases of interstitial lung disease caused by exposure to hard metal. The first case involves a 37-year-old Taiwanese man who had worked at a grinder station for hard metal materials for 12 years without respiratory protective equipment. He experienced a dry cough and exertional dyspnea, and his chest imaging and pathology findings were consistent with the features of usual interstitial pneumonia. Analysis of his lung tissue revealed the presence of tungsten and cobalt. The second case involves a 68-year-old Taiwanese woman, the mother of the first patient, who had hand-washed her son's workwear. She experienced a dry cough and had similar imaging findings to her son. After her son left his job, they both exhibited improved symptoms and lung functions with nintedanib treatment. These findings suggest a diagnosis of HMLD and interstitial lung disease resulting from para-occupational exposure to hard metal dust. CONCLUSIONS: The diagnosis of HMLD relies on obtaining a detailed occupational exposure history. If HMLD is diagnosed, discontinuing exposing to hard metal dusts can lead to improved lung function.

Preservation of vascular endothelial glycocalyx and barrier by activation of adenosine A2A receptor (A2AR) improved renal dysfunction in cirrhotic rats.

Cirrhosis-related hepatic and renal endothelial dysfunction is characterized by macrophage-endothelium adhesion-mediated inflammation, glycocalyx/barrier damage, and impaired vasodilation. Activation of adenosine A2A receptor (A2AR) protects cirrhotic rats from impairment of hepatic microcirculation post hepatectomy. This study evaluates the effects of A2AR activation on the cirrhosis-related hepatic and renal endothelial dysfunction in biliary cirrhotic rats receiving two weeks of A2AR agonist PSB0777 [bile duct ligated (BDL)+PSB0777] treatment. Endothelial dysfunction in cirrhotic liver, renal vessels, and kidney is characterized by downregulation of the A2AR expressions, decreased vascular endothelial vasodilatory (p-eNOS)/anti-inflammatory (IL-10/IL-10R)/barrier [VE-cadherin (CDH5) and ß-catenin (CTNNB1)]/glycocalyx [syndecan-1 (SDC1) and hyaluronan synthase-2 (HAS2)] markers, and increased leukocyte-endothelium adhesion molecules (F4/80, CD68, ICAM-1, and VCAM-1). In BDL rats, PSB0777 treatment improves hepatic and renal endothelial dysfunction, ameliorates portal hypertension, and attenuates renal hypoperfusion by restoring of the vascular endothelial anti-inflammatory, barrier, glycocalyx markers and vasodilatory response as well as inhibiting the leukocyte-endothelium adhesion. In an in vitro study, conditioned medium (CM) of bone marrow-derived macrophage (BMDM) of BDL rats [BMDM-CM (BDL)] induced barrier/glycocalyx damage, which was reversed by the PSB0777 pre-treatment. The A2AR agonist is a potential agent that can simultaneously correct cirrhosis-related hepatic and renal endothelial dysfunction, portal hypertension, renal hypoperfusion, and renal dysfunction.

COVID-19-associated pulmonary aspergillosis is associated with increased in-hospital mortality and prolonged SARS-CoV-2 viral shedding.

BACKGROUND/PURPOSE: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is common in critically ill patients with COVID-19 and is associated with worse outcomes. However, reports on CAPA and its impact on treatment outcomes in Asian populations are limited. METHODS: Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction-confirmed COVID-19 admitted to intensive care units (ICUs) were retrospectively enrolled in this observational study. The incidence rate of CAPA during ICU admission was investigated. The clinical factors associated with CAPA, including corticosteroid exposure, were analyzed. The impact of CAPA on the treatment outcomes and SARS-CoV-2 viral shedding were explored. RESULTS: A total of 72 ICU-admitted patients with COVID-19 were included in the analysis. The incidence rate of CAPA was 15.3% (11/72) in all patients and 23% (11/48) in the mechanically ventilated patients. The median time from ICU admission to CAPA diagnosis was 15 days. A lower fibrinogen level (adjusted odds ratio [aOR], 0.983; 95% confidence interval [CI], 0.967-0.999) was independently associated with CAPA. The patients with CAPA had a higher in-hospital mortality rate (55% vs. 13%, p = 0.001) and a longer SARS-CoV-2 viral shedding time (22 days vs. 16 days, p = 0.037) than those without CAPA. CONCLUSION: Lower serum fibrinogen levels was independently associated with CAPA among the ICU-admitted patients with COVID-19. The patients with CAPA had a higher in-hospital mortality rate and a longer SARS-CoV-2 viral shedding time than those without CAPA.

Nintedanib Inhibits Endothelial Mesenchymal Transition in Bleomycin-Induced Pulmonary Fibrosis via Focal Adhesion Kinase Activity Reduction.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD). Pulmonary fibroblasts play an important role in the development of IPF. Emerging evidence indicates that pulmonary endothelial cells could be the source of pulmonary fibroblasts through endothelial mesenchymal transition (EndoMT), which contributes to pulmonary fibrosis. EndoMT is a complex process in which endothelial cells lose their expression of endothelial markers and give rise to the characteristics of mesenchymal cells, including morphological fibroblast-like change and the expression of mesenchymal markers, which result in cardiac, renal, and dermal fibroses. Furthermore, EndoMT inhibition attenuates pulmonary fibrosis. Herein, we demonstrate that nintedanib, a tyrosine kinase receptor inhibitor, ameliorated murine bleomycin (BLM)-induced pulmonary fibrosis and suppressed the in vivo and in vitro models of EndoMT. We demonstrated that the activity of focal adhesion kinase (FAK), a key EndoMT regulator, increased in murine lung tissues and human pulmonary microvascular endothelial cells after BLM stimulation. Nintedanib treatment inhibited BLM-induced FAK activation and thus suppressed both in vivo and in vitro BLM-induced EndoMT. Importantly, we found that the VEGF/FAK signaling pathway was involved in nintedanib regulating EndoMT. These novel findings help us understand the mechanism and signaling pathway of EndoMT to further develop more efficacious drugs for IPF treatment.