Clinical impact of blood pressure variability in patients with COVID-19 and hypertension.

OBJECTIVE: This study aimed to investigate the relationship between blood pressure variability (BPV) and clinical outcomes in patients with coronavirus disease 2019 (COVID-19) and hypertension. METHODS: A total of 136 patients hospitalized with COVID-19 were enrolled in this study. Patients were grouped according to the presence of hypertension and BPV. Mean arterial pressure (MAP) measured at 8 a.m. and 8 p.m. was analyzed, and BPV was calculated as the coefficient of variation of MAP (MAPCV). High BPV was defined as MAPCV values above the median. We compared the age, level of C-reactive protein (CRP), creatine kinase-MB (CK-MB), N-terminal pro-B type natriuretic peptide (NT-proBNP), creatinine and in-hospital mortality and investigated the relationship among the groups. RESULTS: COVID-19 patients with hypertension were older (70 ± 12 vs. 53 ± 17 years; P < 0.001), had higher levels of CRP (9.4 ± 9.2 vs. 5.3 ± 8.2 mg/dL; P = 0.009), MAPCV (11.4 ± 4.8 vs. 8.9 ± 3.2; P = 0.002), and higher in-hospital mortality (19.6% vs. 5.9%; P = 0.013) than those without hypertension. There was a proportional relationship between BPV and age, levels of CRP, CK-MB, NT-proBNP, creatinine and in-hospital mortality (all, P < 0.05). In Cox regression analysis, advanced age [≥80 years, hazard ratio (HR) 10.4, 95% confidence interval (CI) 2.264-47.772, P = 0.003] and higher MAPCV (HR 1.617, 95% CI, 1.281-2.040, P < 0.001) were significantly associated with in-hospital mortality. CONCLUSION: High BPV in COVID-19 patients with hypertension is significantly associated with in-hospital mortality. Advanced age and systemic inflammation are proportional to high BPV. Additional attention is needed for COVID-19 patients with hypertension and high BPV.

PEGylated nanoparticle albumin-bound steroidal ginsenoside derivatives ameliorate SARS-CoV-2-mediated hyper-inflammatory responses.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on a global scale urges prompt and effective countermeasures. Recently, a study has reported that coronavirus disease-19 (COVID-19), the disease caused by SARS-CoV-2 infection, is associated with a decrease in albumin level, an increase in NETosis, blood coagulation, and cytokine level. Here, we present drug-loaded albumin nanoparticles as a therapeutic agent to resolve the clinical outcomes observed in severe SARS-CoV-2 patients. PEGylated nanoparticle albumin-bound (PNAB) was used to promote prolonged bioactivity of steroidal ginsenoside saponins, PNAB-Rg6 and PNAB-Rgx365. Our data indicate that the application of PNAB-steroidal ginsenoside can effectively reduce histone H4 and NETosis-related factors in the plasma, and alleviate SREBP2-mediated systemic inflammation in the PBMCs of SARS-CoV-2 ICU patients. The engineered blood vessel model confirmed that these drugs are effective in suppressing blood clot formation and vascular inflammation. Moreover, the animal model experiment showed that these drugs are effective in promoting the survival rate by alleviating tissue damage and cytokine storm. Altogether, our findings suggest that these PNAB-steroidal ginsenoside drugs have potential applications in the treatment of symptoms associated with severe SARS-CoV-2 patients, such as coagulation and cytokine storm.

Lung-selective 25-hydroxycholesterol nanotherapeutics as a suppressor of COVID-19-associated cytokine storm.

In response to the coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), global efforts are focused on the development of new therapeutic interventions. For the treatment of COVID-19, selective lung-localizing strategies hold tremendous potential, as SARS-CoV-2 invades the lung via ACE2 receptors and causes severe pneumonia. Similarly, recent reports have shown the association of COVID-19 with decreased 25-hydroxycholesterol (25-HC) and increased cytokine levels. This mechanism, which involves the activation of inflammatory NF-κB- and SREBP2-mediated inflammasome signaling pathways, is believed to play a crucial role in COVID-19 pathogenesis, inducing acute respiratory distress syndrome (ARDS) and sepsis. To resolve those clinical conditions observed in severe SARS-CoV-2 patients, we report 25-HC and didodecyldimethylammonium bromide (DDAB) nanovesicles (25-HC@DDAB) as a COVID-19 drug candidate for the restoration of intracellular cholesterol level and suppression of cytokine storm. Our data demonstrate that 25-HC@DDAB can selectively accumulate the lung tissues and effectively downregulate NF-κB and SREBP2 signaling pathways in COVID-19 patient-derived PBMCs, reducing inflammatory cytokine levels. Altogether, our findings suggest that 25-HC@DDAB is a promising candidate for the treatment of symptoms associated with severe COVID-19 patients, such as decreased cholesterol level and cytokine storm.

Clinical features and prognostic factors of critically ill patients with COVID-19 in Daegu, South Korea: A multi-center retrospective study.

ABSTRACT: To describe the clinical and demographic characteristics of critically ill patients with COVID-19 in Daegu, South Korea, and to explore the risk factors for in-hospital mortality in these patients.Retrospective cohort study of 110 critically ill patients with COVID-19 admitted to the ICU in Daegu, South Korea, between February 18 and April 5, 2020. The final date of follow-up was April 20, 2020.A total of 110 patient medical records were reviewed. The median age was 71 years (interquartile range [IQR] = 63-78 years). During the study period, 47 patients (42.7%) died in the hospital. The most common SARS-CoV-2 infection related complication was acute respiratory distress syndrome (ARDS) in 95 patients (86.4%). Of the 79 patients (71.8%) who received invasive mechanical ventilation, 46 (58.2%) received neuromuscular blockade injection, and 19 (24.1%) received ECMO treatment. All patients received antibiotic injection, 99 patients (90%) received hydroxychloroquine, 96 patients (87.3%) received lopinavir-ritonavir antiviral medication, and 14 patients (12.7%) received other antiviral agents, including darunavir-cobicistat and emtricitabine-tenofovir. In the multivariable logistic regression model, the odds ratio of in-hospital death was higher with APACHE II score (OR = 1.126; 95% CI = 1.014-1.252; P  = .027).The in-hospital mortality rate of critically ill patients with COVID-19 was approximately 40%. Higher APACHE II score at admission was an independent risk factor for death in these patients.

Quantitative Assessment of Chest CT Patterns in COVID-19 and Bacterial Pneumonia Patients: a Deep Learning Perspective.

BACKGROUND: It is difficult to distinguish subtle differences shown in computed tomography (CT) images of coronavirus disease 2019 (COVID-19) and bacterial pneumonia patients, which often leads to an inaccurate diagnosis. It is desirable to design and evaluate interpretable feature extraction techniques to describe the patient's condition. METHODS: This is a retrospective cohort study of 170 confirmed patients with COVID-19 or bacterial pneumonia acquired at Yeungnam University Hospital in Daegu, Korea. The Lung and lesion regions were segmented to crop the lesion into 2D patches to train a classifier model that could differentiate between COVID-19 and bacterial pneumonia. The K-means algorithm was used to cluster deep features extracted by the trained model into 20 groups. Each lesion patch cluster was described by a characteristic imaging term for comparison. For each CT image containing multiple lesions, a histogram of lesion types was constructed using the cluster information. Finally, a Support Vector Machine classifier was trained with the histogram and radiomics features to distinguish diseases and severity. RESULTS: The 20 clusters constructed from 170 patients were reviewed based on common radiographic appearance types. Two clusters showed typical findings of COVID-19, with two other clusters showing typical findings related to bacterial pneumonia. Notably, there is one cluster that showed bilateral diffuse ground-glass opacities (GGOs) in the central and peripheral lungs and was considered to be a key factor for severity classification. The proposed method achieved an accuracy of 91.2% for classifying COVID-19 and bacterial pneumonia patients with 95% reported for severity classification. The CT quantitative parameters represented by the values of cluster 8 were correlated with existing laboratory data and clinical parameters. CONCLUSION: Deep chest CT analysis with constructed lesion clusters revealed well-known COVID-19 CT manifestations comparable to manual CT analysis. The constructed histogram features improved accuracy for both diseases and severity classification, and showed correlations with laboratory data and clinical parameters. The constructed histogram features can provide guidance for improved analysis and treatment of COVID-19.

Early Hydroxychloroquine Administration for Rapid Severe Acute Respiratory Syndrome Coronavirus 2 Eradication.

There are no proven therapeutics for Coronavirus disease 2019 (COVID-19) pneumonia outbreak. We observed and analyzed the clinical efficacy of the most used hydroxychloroquine (HCQ) for 30 days. In this study, administration of HCQ <5 days from diagnosis (odds ratio: 0.111, 95% confidence interval: 0.034 - 0.367, P = 0.001) was the only protective factor for prolonging of viral shedding in COVID-19 patients. Early administration of HCQ significantly ameliorates inflammatory cytokine secretion by eradicating COVID-19, at discharge. Our findings suggest that patients confirmed of COVID-19 infection should be administrated HCQ as soon as possible.

Long-acting nanoparticulate DNase-1 for effective suppression of SARS-CoV-2-mediated neutrophil activities and cytokine storm.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus not previously identified in humans. Globally, the number of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) have risen dramatically. Currently, there are no FDA-approved antiviral drugs and there is an urgency to develop treatment strategies that can effectively suppress SARS-CoV-2-mediated cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. As symptoms progress in patients with SARS-CoV-2 sepsis, elevated amounts of cell-free DNA (cfDNA) are produced, which in turn induce multiple organ failure in these patients. Furthermore, plasma levels of DNase-1 are markedly reduced in SARS-CoV-2 sepsis patients. In this study, we generated recombinant DNase-1-coated polydopamine-poly(ethylene glycol) nanoparticulates (named long-acting DNase-1), and hypothesized that exogenous administration of long-acting DNase-1 may suppress SARS-CoV-2-mediated neutrophil activities and the cytokine storm. Our findings suggest that exogenously administered long-acting nanoparticulate DNase-1 can effectively reduce cfDNA levels and neutrophil activities and may be used as a potential therapeutic intervention for life-threatening SARS-CoV-2-mediated illnesses.

Ferritin Nanocage-Based Methyltransferase SETD6 for COVID-19 Therapy

Abstract The transcription factor nuclear factor-?B (NF-?B) signaling is a mediator of viral infection-mediated inflammation and SET-domain containing 6 (SETD6) is known as a methyltransferase that suppresses the activity of NF-?B signaling. However, the downside of the SETD6 is that it cannot be directly utilized as an inflammatory regulator due to the short half-life and poor intracellular delivery. Here, a ferritin nanocage-based delivery system is presented that can maintain the activity of SETD6 in vivo. According to the analysis of severe COVID-19 patients? peripheral blood mononuclear cells (PBMCs), the SETD6 expression is downregulated while that of NF-?B is upregulated. By engineering the structure of ferritin, a protein scaffold is fabricated in which short ferritin is decorated with cell-penetrating peptide and nuclear-localizing TAT-NBD peptide together with SETD6, termed TFS. The TFS enhances the SETD6 level and reduces the NF-?B signaling in PBMCs of severe COVID-19 patients and subsequently suppresses the cytokine storm. When the TFS is intravenously administered in the cytokine storm mouse model, the survival rate is rescued and the lung tissue damage and cytokine expression are also inhibited. These results indicate that the ferritin nanocage-based peptide delivery system allows stable in vivo delivery and efficient suppression of NF-?B signaling-mediated inflammation.

COVID-19-activated SREBP2 disturbs cholesterol biosynthesis and leads to cytokine storm.

Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients' blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.

Early Hydroxychloroquine Administration for Rapid Severe Acute Respiratory Syndrome Coronavirus 2 Eradication

There are no proven therapeutics for Coronavirus disease 2019 (COVID-19) pneumonia outbreak. We observed and analyzed the clinical efficacy of the most used hydroxychloroquine (HCQ) for 30 days. In this study, administration of HCQ <5 days from diagnosis (odds ratio: 0.111, 95% confidence interval: 0.034 - 0.367, P = 0.001) was the only protective factor for prolonging of viral shedding in COVID-19 patients. Early administration of HCQ significantly ameliorates inflammatory cytokine secretion by eradicating COVID-19, at discharge. Our findings suggest that patients confirmed of COVID-19 infection should be administrated HCQ as soon as possible.

Prognostic Factors for Severe Coronavirus Disease 2019 in Daegu, Korea.

BACKGROUND: Since its first detection in December 2019, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 infection has spread rapidly around the world. Although there have been several studies investigating prognostic factors for severe COVID-19, there have been no such studies in Korea. METHODS: We performed a retrospective observational study of 110 patients with confirmed COVID-19 hospitalized at a tertiary hospital in Daegu, Korea. Demographic, clinical, laboratory, and outcome data were collected and analyzed. Severe disease was defined as a composite outcome of acute respiratory distress syndrome, intensive care unit care, or death. RESULTS: Diabetes mellitus (odds ratio [OR], 19.15; 95% confidence interval [CI], 1.90-193.42; P = 0.012), body temperature ≥ 37.8°C (OR, 10.91; 95% CI, 1.35-88.36; P = 0.025), peripheral oxygen saturation < 92% (OR, 33.31; 95% CI, 2.45-452.22; P = 0.008), and creatine kinase-MB (CK-MB) > 6.3 (OR, 56.84; 95% CI, 2.64-1,223.78, P = 0.010) at admission were associated with higher risk of severe COVID-19. The likelihood of development of severe COVID-19 increased with an increasing number of prognostic factors. CONCLUSION: In conclusion, we found that diabetes mellitus, body temperature ≥ 37.8°C, peripheral oxygen saturation < 92%, and CK-MB > 6.3 are independent predictors of severe disease in hospitalized COVID-19 patients. Appropriate assessment of prognostic factors and close monitoring to provide the necessary interventions at the appropriate time in high-risk patients may reduce the case fatality rate of COVID-19.

Prognostic Accuracy of the SIRS, qSOFA, and NEWS for Early Detection of Clinical Deterioration in SARS-CoV-2 Infected Patients.

BACKGROUND: The case fatality rate of coronavirus disease 2019 (COVID-19) is estimated to be between 4.3% and 11.0%. Currently there is no effective antiviral treatment for COVID-19. Thus, early recognition of patients at high risk is important. METHODS: We performed a retrospective observational study of 110 patients with severe acute respiratory syndrome coronavirus 2 infection. We compared the effectiveness of three scoring systems: the Systemic Inflammatory Response Syndrome (SIRS), quick Sequential Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS) systems, for predicting the prognosis of COVID-19. The area under the receiver operating characteristic curve (AUROC) was used for these assessments, and Kaplan-Meier survival curves were used to identify the cumulative risk for 28-day mortality according to the NEWS stratification. RESULTS: For predicting 28-day mortality, NEWS was superior to qSOFA (AUROC, 0.867 vs. 0.779, P < 0.001), while there was no significant difference between NEWS and SIRS (AUROC, 0.867 vs. 0.639, P = 0.100). For predicting critical outcomes, NEWS was superior to both SIRS (AUROC, 0.918 vs. 0.744, P = 0.032) and qSOFA (AUROC, 0.918 vs. 0.760, P = 0.012). Survival time was significantly shorter for patients with NEWS ≥ 7 than for patients with NEWS < 7. CONCLUSION: Calculation of the NEWS at the time of hospital admission can predict critical outcomes in patients with COVID-19. Early intervention for high-risk patients can thereby improve clinical outcomes in COVID-19 patients.

The Risk of Diabetes on Clinical Outcomes in Patients with Coronavirus Disease 2019: A Retrospective Cohort Study.

BACKGROUND: To determine the role of diabetes mellitus (DM) in the coronavirus disease 2019 (COVID-19), we explored the clinical characteristics of patients with DM and compared risk factors such as age, glycemic control, and medications to those without DM. METHODS: This was a retrospective cohort study of 117 confirmed patients with COVID-19 which conducted at a tertiary hospital in Daegu, South Korea. The primary outcome was defined as the severe and critical outcome (SCO), of which the composite outcomes of acute respiratory distress syndrome, septic shock, intensive care unit care, and 28-day mortality. We analyzed what clinical features and glycemic control-related factors affect the prognosis of COVID-19 in the DM group. RESULTS: After exclusion, 110 participants were finally included. DM patients (n=29) was older, and showed higher blood pressure compared to non-DM patients. DM group showed higher levels of inflammation-related biomarkers and severity score, and highly progressed to SCO. After adjustment with other risk factors, DM increased the risk of SCO (odds ratio [OR], 10.771; P<0.001). Among the DM patients, SCO was more prevalent in elderly patients of ≥70 years old and age was an independent risk factor for SCO in patients with DM (OR, 1.175; P=0.014), while glycemic control was not. The use of medication did not affect the SCO, but the renin-angiotensin system inhibitors showed protective effects against acute cardiac injury (OR, 0.048; P=0.045). CONCLUSION: The COVID-19 patients with DM had higher severity and resulted in SCO. Intensive and aggressive monitoring of COVID-19 clinical outcomes in DM group, especially in elderly patients is warranted.

Clinical Features and Outcomes of 98 Patients Hospitalized with SARS-CoV-2 Infection in Daegu, South Korea: A Brief Descriptive Study.

Although some information on the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a few selected cases has been reported, data on the clinical characteristics and outcomes of patients hospitalized therewith in South Korea are lacking. We conducted a retrospective single-center study of 98 consecutive hospitalized patients with confirmed SARS-CoV-2 infection at Yeungnam University Medical Center in Daegu, South Korea. Sixty patients were women (61.2%), and the mean age was 55.4±17.1 years. Thirteen patients (13.3%) were treated in the intensive care unit (ICU). The mean interval from symptom onset to hospitalization was 7.7±4.5 days. Patients who received ICU care were significantly older and were more likely to have diabetes mellitus. The National Early Warning Score on the day of admission was significantly higher in patients requiring ICU care. Acute respiratory distress syndrome (13/13 patients; 100%), septic shock (9/13; 69.2%), acute cardiac injury (9/13; 69.2%), and acute kidney injury (8/13; 61.5%) were more common in patients who received ICU care. All patients received antibiotic therapy, and most (97/98 patients; 99.0%) received antiviral therapy (lopinavir/ritonavir). Hydroxychloroquine was used in 79 patients (80.6%), and glucocorticoid therapy was used in 18 patients (18.4%). In complete blood counts, lymphopenia was the most common finding (40/98 patients; 40.8%). Levels of all proinflammatory cytokines were significantly higher in ICU patients. As of March 29, 2020, the mortality rate was 5.1%. Here, we report the clinical characteristics and laboratory findings of SARS-CoV-2 patients in South Korea up to March 29, 2020.