Abstract
Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that leads to severe respiratory failure (RF). It is known that host exposure to viral infection triggers an ...iron-lowering response to mitigate pathogenic load and tissue damage. However, the association between host iron-lowering response and COVID-19 severity is not clear. This two-center observational study of 136 adult hospitalized COVID-19 patients analyzed the association between disease severity and initial serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) levels. Serum iron levels were significantly lower in patients with mild RF than in the non-RF group; however, there were no significant differences in iron levels between the non-RF and severe RF groups, depicting a U-shaped association between serum iron levels and disease severity. TIBC levels decreased significantly with increasing severity; consequently, TSAT was significantly higher in patients with severe RF than in other patients. Multivariate analysis including only patients with RF adjusted for age and sex demonstrated that higher serum iron and TSAT levels were independently associated with the development of severe RF, indicating that inadequate response to lower serum iron might be an exacerbating factor for COVID-19.
The increasing requirement of mechanical ventilation (MV) due to the novel coronavirus disease (COVID-19) is still a global threat. The aim of this study is to identify markers that can easily ...stratify the impending use of MV in the emergency room (ER). A total of 106 patients with COVID-19 requiring oxygen support were enrolled. Fifty-nine patients were provided MV 0.5 h (interquartile range: 0.3 to 1.4) post-admission. Clinical and laboratory data before intubation were collected. Using a multivariate logistic regression model, we identified four markers associated with the impending use of MV, including the ratio of peripheral blood oxygen saturation to fraction of inspired oxygen (SpO2/FiO2 ratio), alanine aminotransferase, blood glucose (BG), and lymphocyte counts. Among these markers, SpO2/FiO2 ratio and BG, which can be measured easily and immediately, showed higher accuracy (AUC: 0.88) than SpO2/FiO2 ratio alone (AUC: 0.84), despite no significant difference (DeLong test: P = 0.591). Moreover, even in patients without severe respiratory failure (SpO2/FiO2 ratio > 300), BG (> 138 mg/dL) was predictive of MV use. Measuring BG and SpO2/FiO2 ratio may be a simple and versatile new strategy to accurately identify ER patients with COVID-19 at high risk for the imminent need of MV.
Cardioprotective effect of prostaglandin-E2 receptor-4 (EP4) stimulation on the ischemic heart has been demonstrated. Its effect on the heart affected by myocarditis, however, remains uncertain. In ...this study, we investigated therapeutic effect of EP4 stimulant using a mouse model of autoimmune myocarditis (EAM) that progresses to dilated cardiomyopathy (DCM). EP4 was present in the hearts of EAM mice. Treatment with EP4 agonist (ONO-0260164: 20 mg/kg/day) improved an impaired left ventricular (LV) contractility and reduction of blood pressure on day 21, a peak myocardial inflammation. Alternatively, DCM phenotype, characterized by LV dilation, LV systolic dysfunction, and collagen deposition, was observed on day 56, along with activation of matrix metalloproteinase (MMP)-2 critical for myocardial extracellular matrix disruption, indicating an important molecular mechanism underlying adverse ventricular remodeling after myocarditis. Continued treatment with ONO-0260164 alleviated the DCM phenotype, but this effect was counteracted by its combination with a EP4 antagonist. Moreover, ONO-0260164 inhibited in vivo proteolytic activity of MMP-2 in association with up-regulation of tissue inhibitor of metalloproteinase (TIMP)-3. EP4 stimulant may be a promising and novel therapeutic agent that rescues cardiac malfunction during myocarditis and prevents adverse ventricular remodeling after myocarditis by promoting the TIMP-3/MMP-2 axis.
We aimed to develop a method to determine the CT score that can be easily obtained from CT images and examine its prognostic value for severe COVID pneumonia. Patients with COVID pneumonia who ...required ventilatory management by intubation were included. CT score was based on anatomical information in axial CT images and were divided into three sections of height from the apex to the bottom. The extent of pneumonia in each section was rated from 0 to 5 and summed. The primary outcome was the prediction of patients who died or were managed on extracorporeal membrane oxygenation (ECMO) based on the CT score at admission. Of the 71 patients included, 12 (16.9%) died or required ECMO management, and the CT score predicted death or ECMO management with ROC of 0.718 (0.561-0.875). The death or ECMO versus survival group (median quartiles) had a CT score of 17.75 (14.75-20) versus 13 (11-16.5), p = 0.017. In conclusion, a higher score on our generated CT score could predict the likelihood of death or ECMO management. A CT score at the time of admission allows for early preparation and transfer to a hospital that can manage patients who may need ECMO.
A 65-yr-old man visited a primary care hospital with a continued fever of 38°C for 3 days. As his fever did not improve until 8 days after, he was admitted into another acute care hospital, where his ...respiratory condition rapidly worsened. Therefore, the patient was transferred to our hospital. On the day of transfer (day 1), he was started on mechanical ventilation. COVID-19 was diagnosed using a polymerase chain reaction assay 6 days after admission (day 6). The rehabilitation therapy was begun on day 6. The initial rehabilitation programs focused on positioning and postural drainage. The patient was extubated on day 19, and he began standing and stepping on the same day. Gait exercises began on day 22, and endurance training was initiated on day 28. The patient was discharged from our hospital on day 34 as he met the physical function milestones. One month after discharge, the Medical Research Council sum score and Barthel Index had each improved; therefore, muscle strength and daily activities had returned to normal. It was assumed that mobilization should be performed as soon as possible after the end of sedation during the acute phase of severe COVID-19 infection in patients receiving mechanical ventilation.
Background The outcomes of coronavirus disease 2019 (COVID-19) treatment have improved due to vaccination and the establishment of better treatment regimens. However, the emergence of variants of the ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, and the corresponding changes in the characteristics of the disease present new challenges in patient management. This study aimed to analyze predictors of COVID-19 severity caused by the delta and omicron variants of SARS-CoV-2. Methods We retrospectively analyzed the data of patients who were admitted for COVID-19 at Yokohama City University Hospital from August 2021 to March 2022. Results A total of 141 patients were included in this study. Of these, 91 had moderate COVID-19, whereas 50 had severe COVID-19. There were significant differences in sex, vaccination status, dyspnea, sore throat symptoms, and body mass index (BMI) (p <0.0001, p <0.001, p <0.001, p = 0.02, p< 0.0001, respectively) between the moderate and severe COVID-19 groups. Regarding comorbidities, smoking habit and renal dysfunction were significantly different between the two groups (p = 0.007 and p = 0.01, respectively). Regarding laboratory data, only LDH level on the first day of hospitalization was significantly different between the two groups (p<0.001). Multiple logistic regression analysis revealed that time from the onset of COVID-19 to hospitalization, BMI, smoking habit, and LDH level were significantly different between the two groups (p<0.03, p = 0.039, p = 0.008, p<0.001, respectively). The cut-off value for the time from onset of COVID-19 to hospitalization was four days (sensitivity, 0.73; specificity, 0.70). Conclusions Time from the onset of COVID-19 to hospitalization is the most important factor in the prevention of the aggravation of COVID-19 caused by the delta and omicron SARS-CoV-2 variants. Appropriate medical management within four days after the onset of COVID-19 is essential for preventing the progression of COVID-19, especially in patients with smoking habits.
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with a poor prognosis. Fibroblast proliferation amplifies extracellular matrix deposition and increases angiogenesis. Vascular endothelial ...growth factor (VEGF) is one of the most potent angiogenic factors. VEGF interacts with VEGF receptors (VEGFR1 and VEGFR2). A previous study showed that VEGFR1 tyrosine kinase (TK) signaling induced blood flow recovery mediated by bone marrow (BM)-derived stem cells. We hypothesized that VEGFR1-TK signaling might be related to pulmonary fibrosis.
Six-week-old male C57Bl/6 wild-type (WT) mice and VEGFR1 TK knockout mice (TKKO mice) were treated with a single intratracheal injection of bleomycin (BLM; 0.1 μg in 50 μl saline) or vehicle (saline; 50 μl). Lung fibrosis was evaluated by histology, real-time PCR and ELISA for pro-fibrotic factors, and assessment of lung mechanics.
The fibrotic area in the lung and the lung elastance were significantly reduced in TKKO mice (P < 0.01). The expression of the fibrosis-related factors type I collagen, S100A4, and transforming growth factor (TGF)-β was also significantly reduced in TKKO mice on day 21 after BLM injection. TKKO mice also had significantly lower levels of stromal cell-derived factor (SDF)-1 in the lungs and plasma on days 14 and 21 after BLM treatment (P < 0.05). Moreover, the expression of C-X-C chemokine receptor type 7 (CXCR7) and CXCR4, the receptors for SDF-1, was also suppressed in TKKO mice. Immunohistochemical analysis showed that treatment with a CXCR4 antibody decreased the accumulation of VEGFR1+ cells in the lung in WT mice but not in TKKO mice.
These results suggest that VEGFR1 TK signaling promotes BLM-induced pulmonary fibrosis by activating the SDF-1/CXCR4 axis in infiltrating VEGFR1+ cells.
Cyclooxygenase (COX)‐2 is known to correlate with poor cancer prognosis and to contribute to tumor metastasis. However, the precise mechanism of this phenomenon remains unknown. We have previously ...reported that host stromal prostaglandin E2 (PGE2)–prostaglandin E2 receptor (EP)3 signaling appears critical for tumor‐associated angiogenesis and tumor growth. Here we tested whether the EP3 receptor has a critical role in tumor metastasis. Lewis lung carcinoma (LLC) cells were intravenously injected into WT mice and mice treated with the COX‐2 inhibitor NS‐398. The nonselective COX inhibitor aspirin reduced lung metastasis, but the COX‐1 inhibitor SC560 did not. The expression of matrix metalloproteinases (MMP)‐9 and vascular endothelial growth factor (VEGF)‐A was suppressed in NS‐398‐treated mice compared with PBS‐treated mice. Lungs containing LLC colonies were markedly reduced in EP3 receptor knockout (EP3−/−) mice compared with WT mice. The expression of MMP‐9 and VEGF‐A was downregulated in metastatic lungs of EP3−/− mice. An immunohistochemical study revealed that MMP‐9‐expressing endothelial cells were markedly reduced in EP3−/− mice compared with WT mice. When HUVEC were treated with agonists for EP1, EP2, EP3, or EP4, only the EP3 agonist enhanced MMP‐9 expression. These results suggested that EP3 receptor signaling on endothelial cells is essential for the MMP‐9 upregulation that enhances tumor metastasis and angiogenesis. An EP3 receptor antagonist may be useful to protect against tumor metastasis. (Cancer Sci 2009; 100: 2318–2324)
The coronavirus disease 2019 (COVID-19) pandemic rapidly increases the use of mechanical ventilation (MV). Such cases further require extracorporeal membrane oxygenation (ECMO) and have a high ...mortality.
We aimed to identify prognostic biomarkers pathophysiologically reflecting future deterioration of COVID-19.
Clinical, laboratory, and outcome data were collected from 102 patients with moderate to severe COVID-19. Interleukin (IL)-6 level and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA copy number in plasma were assessed with ELISA kit and quantitative PCR.
Twelve patients died or required ECMO owing to acute respiratory distress syndrome despite the use of MV. Among various variables, a ratio of oxygen saturation to fraction of inspired oxygen (SpO2/FiO2), IL-6, and SARS-CoV-2 RNA on admission before intubation were strongly predictive of fatal outcomes after the MV use. Moreover, among these variables, combining SpO2/FiO2, IL-6, and SARS-CoV-2 RNA showed the highest accuracy (area under the curve: 0.934). In patients with low SpO2/FiO2 (< 261), fatal event-rate after the MV use at the 30-day was significantly higher in patients with high IL-6 (> 49 pg/mL) and SARS-CoV-2 RNAaemia (> 1.5 copies/μL) compared to those with high IL-6 or RNAaemia or without high IL-6 and RNAaemia (88% vs. 22% or 8%, log-rank test P = 0.0097 or P < 0.0001, respectively).
Combining SpO2/FiO2 with high IL-6 and SARS-CoV-2 RNAaemia which reflect hyperinflammation and viral overload allows accurately and before intubation identifying COVID-19 patients at high risk for ECMO use or in-hospital death despite the use of MV.
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