Inflammation In Coronavirus Disease 2019 Research Articles

Obesity, Inflammation, and Clinical Outcomes in COVID-19: A Multicenter Prospective Cohort Study.

Obesity is a risk factor for coronavirus disease 2019 (COVID-19)-related outcomes; however, the mechanism remains unclear. The objective of this analysis was to determine whether inflammation mediates the association between obesity and COVID-19 outcomes. The International Study of Inflammation in Covid-19 (ISIC): A Prospective Multi-Center Observational Study Examining the Role of Biomarkers of Inflammation in Predicting Covid-19 Related Outcomes in Hospitalized Patients. Ten hospitals in the United States and Europe. Adults hospitalized specifically for COVID-19 between February 1, 2020, through October 19, 2022. Inflammatory biomarkers, including soluble urokinase plasminogen activator receptor (suPAR), were measured at admission. Associations were examined between body-mass index (BMI, kg/m2) and a composite of death, need for mechanical ventilation, and renal replacement therapy, stratified by pre- and post-Omicron variants. The contribution of inflammation to the relationship between obesity and outcomes was assessed. Among 4644 participants (mean age 59.3, 45.6% male, 21.8% BMI≥35), those with BMI>40 (n=485) had 55% higher odds of the composite outcome (95% CI[1.21 to 1.98]) compared to non-obese individuals (BMI<30, n=2358) in multivariable analysis. In multiple mediation analysis, only suPAR remained a significant mediator between BMI and composite outcome. Associations were amplified for participants younger than 65 years and with pre-Omicron variants. Obesity is associated with worse outcomes in COVID-19, notably in younger participants and in the pre-Omicron era. Inflammation, as measured by suPAR, is a significant mediator of the association between obesity and COVID-19 outcomes.

Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies.

The coronavirus disease 2019 (COVID-19) pandemic triggered an unprecedented concentration of economic and research efforts to generate knowledge at unequalled speed on deregulated interferon type I signalling and nuclear factor kappa light chain enhancer in B-cells (NF-κB)-driven interleukin (IL)-1β, IL-6, IL-18 secretion causing cytokine storms. The translation of the knowledge on how the resulting systemic inflammation can lead to life-threatening complications into novel treatments and vaccine technologies is underway. Nevertheless, previously existing knowledge on the role of cytoplasmatic or circulating self-DNA as a pro-inflammatory damage-associated molecular pattern (DAMP) was largely ignored. Pathologies reported 'de novo' for patients infected with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 to be outcomes of self-DNA-driven inflammation in fact had been linked earlier to self-DNA in different contexts, e.g., the infection with Human Immunodeficiency Virus (HIV)-1, sterile inflammation, and autoimmune diseases. I highlight particularly how synergies with other DAMPs can render immunogenic properties to normally non-immunogenic extracellular self-DNA, and I discuss the shared features of the gp41 unit of the HIV-1 envelope protein and the SARS-CoV 2 Spike protein that enable HIV-1 and SARS-CoV-2 to interact with cell or nuclear membranes, trigger syncytia formation, inflict damage to their host's DNA, and trigger inflammation - likely for their own benefit. These similarities motivate speculations that similar mechanisms to those driven by gp41 can explain how inflammatory self-DNA contributes to some of most frequent adverse events after vaccination with the BNT162b2 mRNA (Pfizer/BioNTech) or the mRNA-1273 (Moderna) vaccine, i.e., myocarditis, herpes zoster, rheumatoid arthritis, autoimmune nephritis or hepatitis, new-onset systemic lupus erythematosus, and flare-ups of psoriasis or lupus. The hope is to motivate a wider application of the lessons learned from the experiences with COVID-19 and the new mRNA vaccines to combat future non-COVID-19 diseases.

Coagulation and Inflammation in COVID-19: Reciprocal Relationship between Inflammatory and Coagulation Markers.

The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), formerly known as 2019-nCoV. Numerous cellular and biochemical issues arise after COVID-19 infection. The severe inflammation that is caused by a number of cytokines appears to be one of the key hallmarks of COVID-19. Additionally, people with severe COVID-19 have coagulopathy and fulminant thrombotic events. We briefly reviewed the COVID-19 disease at the beginning of this paper. The inflammation and coagulation markers and their alterations in COVID-19 illness are briefly discussed in the parts that follow. Next, we talked about NETosis, which is a crucial relationship between coagulation and inflammation. In the end, we mentioned the two-way relationship between inflammation and coagulation, as well as the factors involved in it. We suggest that inflammation and coagulation are integrated systems in COVID-19 that act on each other in such a way that not only inflammation can activate coagulation but also coagulation can activate inflammation.

Paradigm of immune dysregulation in coronavirus disease-2019 infection

The coronavirus disease 2019 (COVID-19) pandemic cost 7–8 million deaths worldwide, creating an unprecedented health and economic crisis. Affecting 700 million people globally, the magnitude of this pandemic is far from anything that humanity has encountered in recent times. A detailed investigation revealed that more than the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the hyperactive immune system mediated injury as the real cause of mortality. Cytokine storm following viral infection leads to the surge of proinflammatory cytokines resulting in acute respiratory distress syndrome (ARDS) and lung injury. Anti-inflammatory intervention with anti-interleukin-6 (anti-IL-6) receptor monoclonal antibodies (mAbs; e.g., sarilumab and tocilizumab) and anti-IL-6 mAbs (i.e., siltuximab) and/or steroid-based approach leads to substantial protection and prevent death thereby implying the role of inflammation in COVID-19. In this review, the authors have summarized the dysregulated immune system in COVID-19 infection, investigating in detail the virus-host immune cross talks and presenting the possibilities of therapeutic intervention.

Cardiac deceleration capacity is associated with severity of inflammation in COVID-19

PurposeIn this pilot study, we investigated the cardiac autonomic activity of coronavirus disease 2019 (COVID-19)-infected hospitalized patients. COVID-19 is characterized by cough, fever, and dyspnea, which in some severe cases can lead to hypoxia, respiratory failure, and shock. Since breathing disorders and pulmonary diseases are tightly linked to autonomic dysfunction, we analyzed the cardiac autonomic activity by measuring the deceleration capacity (DC) in COVID-19 patients.MethodsIn 14 adults (4 men and 10 women) with a median age of 63.5 years and positive for SARS-CoV-2 by polymerase chain reaction (PCR) with severe symptoms requiring hospital treatment, a high-resolution digital 30 min electrocardiogram (ECG) in Frank leads configuration was performed in a resting supine position within the first 48 h after hospital admission. DC was assessed using validated software and associated with several markers of inflammation and clinical course.ResultsThe study revealed a significant association between reduced DC (≤ 2.5 ms) and older age (74 years) in COVID-19 patients, compared to those with a higher DC > 2.5 ms (56.5 years). However, the duration of hospitalization was similar for both groups. There was a nonsignificant trend towards a higher maximum viral load in patients with reduced DC. Further, patients with a DC ≤ 2.5 ms showed higher levels of inflammatory markers such as C-reactive protein (CRP) and procalcitonin (PCT), as well as leukocytosis, compared to patients with a DC > 2.5 ms. Also, the COVID-19-severity marker ferritin was significantly elevated in patients with lower DC. Other markers associated with COVID-19, such as lactate dehydrogenase (LDH) and creatine kinase (CK), exhibited comparable levels in both groups.ConclusionsReduced DC (≤ 2.5 ms) was significantly associated with older age, increased inflammatory markers, and elevated ferritin in patients with COVID-19. These findings suggest that DC might serve as a valuable indicator for predicting the risk of severe inflammation in COVID-19 and possibly complications associated with this disease, such as heart failure. Further studies are needed to confirm these observations and clarify the clinical significance of DC in COVID-19 and other infectious diseases.

Assessing the gene expression of the adenosine 5'-monophosphate-activated protein kinase (AMPK) and its relation with the IL-6 and IL-10 plasma levels in COVID-19 patients.

Metabolic dysregulation and excessive inflammation are implicated in the pathogenesis of the highly infectious disease of coronavirus disease 2019 (COVID-19), which is caused by a newly emerging coronavirus (i.e., severe acute respiratory syndrome-coronavirus 2; SARS-CoV-2). The adenosine 5'-monophosphate-activated protein kinase (AMPK), an energy sensor regulating the metabolic pathways in diverse cells, exerts a regulatory role in the immune system. This study aims to examine the mRNA expression level of AMPK and the plasma levels of interleukin-6 (IL-6) and IL-10 cytokines in patients with different grades of COVID-19. Peripheral blood was collected from 60 patients with COVID-19 (Moderate, severe, and critical). The plasma levels of IL-6 and IL-10 were quantified by enzyme-linked immunosorbent assay (ELISA), and the mRNA expression level of AMPK was determined using real-time PCR. The results showed that the plasma levels of IL-6 increased significantly in critical and severe patients compared to moderate cases of COVID-19 (P < 0.001). Moreover, IL-10 plasma concentrations were significantly higher in critical and severe cases than in moderate cases of COVID-19 (P < 0.01 and P < 0.05, respectively). Also, the gene expression of AMPK was meaningfully enhanced in critical patients relative to moderate and severe cases of COVID-19, in order (P < 0.001 and P < 0.01, respectively). There was a positive association between AMPK gene expression and plasma levels of IL-6 and IL-10 (P = 0.006, r = 0.348, P = 0.028, r = 0.283, respectively). Increasing AMPK gene expression is likely a necessary effort of the immune system to inhibit inflammation in critical COVID-19. However, this effort seems to be inadequate, probably due to factors that induce inflammation, like erythrocyte sedimentation rate (ESR) and IL-6.

Evaluation of DPP4/CD26 Potential Role for the Management of Inflammation in COVID-19 Patients

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is re-sponsible for Coronavirus Disease 2019 (COVID-19) pandemic. Cell entry of the virus can be me-diated by several enzymes, such as ACE-2, DPP4/CD26, and TMPRSS2, upon viral membrane fu-sion through SARS-CoV-2 envelope spike glycoproteins. In docked molecular complexes, DPP4/CD26 functional receptors and viral spike proteins have a large interface, potentially leading to inflammation in severe COVID-19. Objective: The aim of this study is to review the role of DPP4/CD26 in the immune system and its effects on the production of cytokine storms in COVID-19. Furthermore, we hypothesize that tar-geting DPP4/CD26 as a therapeutic strategy could reduce the inflammatory complications of SARS-CoV-2 infection. Methods: The current review was conducted using keywords such as COVID-19, SARS-CoV-2, dipeptidyl peptidase-4, CD26, cytokine storm, and treatment to search for articles in Google Scholar and PubMed databases that were specifically oriented towards our objectives. Results: The regulation or inhibition of DPP4/CD26 might affect one or more stages in COVID-19 immuno- pathogenesis due to its associations with many immunological functions, such as modulat-ing the NF-kB pathway, upregulating CD86 expression, activating proliferation of T cells, and in-fluencing the antiviral response and cytokine storm in COVID-19. In this regard, the applications of DPP4/CD26 inhibitors, DPP4/CD26 siRNAs, and CD26 antibodies have been demonstrated to pre-vent cytokine storms and airway inflammation. Conclusion: It is suggested to utilize novel technologies such as CRISPR/Cas and chimeric antigen receptor T cells, based on their many advantages, to increase the sensitivity and specificity of future treatment methods.

Aggregate Index of Systemic Inflammation (AISI), Disease Severity, and Mortality in COVID-19: A Systematic Review and Meta-Analysis.

Combined indices of different haematological cell types appear to be particularly promising for investigating the link between systemic inflammation and coronavirus disease 2019 (COVID-19). We conducted a systematic review and meta-analysis to assess the aggregate index of systemic inflammation (AISI), an emerging index derived from neutrophil, monocyte, platelet, and lymphocyte counts, in hospitalized COVID-19 patients with different disease severity and survival status. We searched electronic databases between the 1st of December 2019 and the 10th of June 2023 and assessed the risk of bias and the certainty of evidence. In 13 studies, severe disease/death was associated with significantly higher AISI values on admission vs. non-severe disease/survival (standard mean difference (SMD) = 0.68, 95% CI 0.38 to 0.97, p < 0.001). The AISI was also significantly associated with severe disease/death in five studies reporting odds ratios (4.39, 95% CI 2.12 to 9.06, p ˂ 0.001), but not in three studies reporting hazard ratios (HR = 1.000, 95% CI 0.999 to 1.002, p = 0.39). The pooled sensitivity, specificity, and area under the curve values for severe disease/death were 0.66 (95% CI 0.58 to 0.73), 0.78 (95% CI 0.73 to 0.83), and 0.79 (95% CI 0.76 to 0.83), respectively. Our study has shown that the AISI on admission can effectively discriminate between patients with different disease severity and survival outcome (PROSPERO registration number: CRD42023438025).

NETosis promotes chronic inflammation and fibrosis in systemic lupus erythematosus and COVID-19

Pulmonary fibrosis, a serious complication of systemic lupus erythematosus (SLE) and coronavirus disease 2019 (COVID-19), leads to irreversible lung damage. However, the underlying mechanism of this condition remains unclear. In this study, we revealed the landscape of transcriptional changes in lung biopsies from individuals with SLE, COVID-19-induced pulmonary fibrosis, and idiopathic pulmonary fibrosis (IPF) using histopathology and RNA sequencing, respectively. Despite the diverse etiologies of these diseases, lung expression of matrix metalloproteinase genes in these diseases showed similar patterns. Particularly, the differentially expressed genes were significantly enriched in the pathway of neutrophil extracellular trap formation, showing similar enrichment signature between SLE and COVID-19. The abundance of Neutrophil extracellular traps (NETs) was much higher in the lungs of individuals with SLE and COVID-19 compared to those with IPF. In-depth transcriptome analyses revealed that NETs formation pathway promotes epithelial-mesenchymal transition (EMT). Furthermore, stimulation with NETs significantly up-regulated α-SMA, Twist, Snail protein expression, while decreasing the expression of E-cadherin protein in vitro. This indicates that NETosis promotes EMT in lung epithelial cells. Given drugs that are efficacious in degrading damaged NETs or inhibiting NETs production, we identified a few drug targets that were aberrantly expressed in both SLE and COVID-19. Among these targets, the JAK2 inhibitor Tofacitinib could effectively disrupted the process of NETs and reversed NET-induced EMT in lung epithelial cells. These findings support that the NETs/EMT axis, activated by SLE and COVID-19, contributes to the progression of pulmonary fibrosis. Our study also highlights that JAK2 as a potential target for the treatment of fibrosis in these diseases.

Inflammation in COVID-19 and the Effects of Non-Pharmacological Interventions during the Pandemic: A Review

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic that hit the health systems worldwide hard, causing a collapse of healthcare systems. One of the main problems of this new virus is the high inflammatory response it provokes, which is the cause of much of the symptoms. Different pharmacological approaches tried to stop the advance of the pandemic, but it seems that only vaccines are the solution. In this line, different nonpharmacological approaches have been made in order to improve symptomatology, contagion, and spread of COVID-19, the principal factors being the physical activity, nutrition, physiotherapy, psychology, and life patterns. The SARS-CoV-2 virus produces a disproportionate inflammatory response in the organism of the guest and causes complications in this that can end the life of the patient. It has been possible to see how different nonpharmacological interventions based on physical activity, nutritional, psychological, and physical therapy, and lifestyle changes can be functional tools to treat this inflammation. Thus, in the present review, we aim to provide an overview of the role of inflammation in COVID-19 and the nonpharmacological interventions related to it.

Abstract 14833: Senescent Endothelial Cells Are Highly Susceptible to SARS-CoV-2 Infection, Which Might Account for the Aggravation of COVID-19 in the Elderly

Introduction: The pandemic of coronavirus disease 2019 (COVID-19), induced by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has posed a global health emergency. COVID-19 vaccines are certainly effective to prevent infection, severe disease, and hospitalization; however, its spreading remains to be uncontrolled worldwide. The striking feature of COVID-19 is the high mortality in the elderly; every 1,000 people infected with SARS-CoV-2, around 116 will die if they are mid-seventies or older, while little will die if they are under the age of 50. Though elderly is more fragile than younger people in general, this substantial difference in mortality strongly suggest a specific factor(s) that aggravate the disease in elder people. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Hypothesis: Senescent endothelial cells are highly susceptible to SARS-CoV-2 infection. Methods: We experimentally investigated the SARS-CoV-2 infection in ECs, and performed a comparative analysis for post-infection molecular events using young and replicative senescent ECs. Results: We identify that; 1) SARS-CoV-2 infects ECs largely through endocytosis, 2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, possibly through enhanced caveolae-mediated endocytosis, 3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, 4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in young ECs, which might causes further exacerbated dysfunction in senescent ECs, 5) SARS-CoV-2 infection significantly affected coagulation cascade only in senescent ECs. Conclusions: These data strongly suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.

Role of fecal calprotectin as a hypoxic intestinal damage biomarker in COVID-19 patients

BackgroundGastrointestinal manifestations of coronavirus disease 2019 (COVID-19) appear to be substantial. Fecal calprotectin is a promising biomarker in COVID-19 associated gastrointestinal inflammation; however, its role in the severity of COVID-19 remains limited. We conducted a study to analyze the relationship between the severity of COVID-19 and hypoxic intestinal damage.MethodsWe assessed the severity of 44 hospitalized COVID-19 pneumonia patients based on the PaO2/FiO2 (P/F) ratio. Inflammatory markers were measured from blood samples, and fecal calprotectin was obtained from stool samples.ResultsMedian levels of fecal calprotectin in COVID-19 patients involved in this study (n = 44) were found to be markedly elevated along with the severity of hypoxemia, as seen in the non-acute respiratory distress syndrome (ARDS) group 21.4 µg/g (5.2–120.9), mild ARDS 54.30 µg/g (5.2–1393.7), moderate ARDS 169.6 µg/g (43.4–640.5), and severe ARDS 451.6 µg/g (364.5–538.6). We also found significant differences in fecal calprotectin levels based on the severity of ARDS (P < 0.001), and although the patients were divided into ARDS and non-ARDS groups (P < 0.001). Furthermore, we found a strong negative correlation between the P/F ratio and fecal calprotectin levels (r = − 0.697, P < 0.001).ConclusionOur findings support the potential role of fecal calprotectin as a biomarker of intestinal inflammation in COVID-19 as a consequence of hypoxic intestinal damage and as suggested by the reduced P/F ratio.

Senescent endothelial cells are predisposed to SARS-CoV-2 infection and subsequent endothelial dysfunction

The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains to spread worldwide. COVID-19 is characterized by the striking high mortality in elderly; however, its mechanistic insights remain unclear. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Here, we experimentally investigated the SARS-CoV-2 infection in cultured human ECs, and performed a comparative analysis for post-infection molecular events using early passage and replicative senescent ECs. We found that; (1) SARS-CoV-2 infects ECs but does not replicate and disappears in 72 hours without causing severe cell damage, (2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, (3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, (4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in early passage ECs, which might causes further exacerbated dysfunction in senescent ECs. These data suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.

Relationship between Procalcitonin Levels (PCT) and Disease Severity in Hospitalized Patients Confirmed Positive for COVID-19

Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This disease attacks the respiratory tract and spreads rapidly almost throughout the world, hence, WHO has declared COVID-19 as a global pandemic. The presence of inflammation and bacterial co-infection in COVID-19 hospitalized patients can increase procalcitonin (PCT) levels as a biomarker of inflammation. Elevated PCT levels are also associated with disease severity. The objective of this study is to determine the relationship between PCT levels and disease severity in hospitalized patients who are confirmed positive for COVID-19. This research method is analytic observational with cross sectional design. The sample is in the form of medical record data for 180 COVID-19 patients who are hospitalized at Bhayangkara Tk. I Raden Said Sukanto Hospital, Jakarta for the period July-December 2020. The relationship between PCT levels and disease severity was statistically analyzed using the Chi Square test. The results of this study were 109 (60.6%) men and 71 (39.4%) women with the highest age group being 46-59 years. The average PCT level was 10.38 ng/mL with the lowest level of 0.01 ng/mL and the highest level of 282.00 ng/mL. PCT levels &lt;0.5 ng/mL were discovered in 111 patients (61.7%) and PCT levels 0.5 ng/mL in 69 patients (38.3%). The severity of disease in mild-moderate illness was 87 patients (48.4%), severe was 35 patients (19.4%), and critical was 58 patients (32.2%). The Chi Square test showed that there was a relationship between PCT levels and disease severity in COVID-19 patients (p = 0.000). The higher the PCT level, the higher the severity of the disease, thus, PCT can be used as an indicator to see the severity of the disease.

Heparanase Blockade as a Novel Dual-Targeting Therapy for COVID-19.

ABSTRACTThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused over 5 million deaths worldwide. Pneumonia and systemic inflammation contribute to its high mortality. Many viruses use heparan sulfate proteoglycans as coreceptors for viral entry, and heparanase (HPSE) is a known regulator of both viral entry and inflammatory cytokines. We evaluated the heparanase inhibitor Roneparstat, a modified heparin with minimum anticoagulant activity, in pathophysiology and therapy for COVID-19. We found that Roneparstat significantly decreased the infectivity of SARS-CoV-2, SARS-CoV-1, and retroviruses (human T-lymphotropic virus 1 [HTLV-1] and HIV-1) in vitro. Single-cell RNA sequencing (scRNA-seq) analysis of cells from the bronchoalveolar lavage fluid of COVID-19 patients revealed a marked increase in HPSE gene expression in CD68+ macrophages compared to healthy controls. Elevated levels of HPSE expression in macrophages correlated with the severity of COVID-19 and the expression of inflammatory cytokine genes, including IL6, TNF, IL1B, and CCL2. In line with this finding, we found a marked induction of HPSE and numerous inflammatory cytokines in human macrophages challenged with SARS-CoV-2 S1 protein. Treatment with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-mediated inflammatory cytokine release from human macrophages, through disruption of NF-κB signaling. HPSE knockdown in a macrophage cell line also showed diminished inflammatory cytokine production during S1 protein challenge. Taken together, this study provides a proof of concept that heparanase is a target for SARS-CoV-2-mediated pathogenesis and that Roneparstat may serve as a dual-targeted therapy to reduce viral infection and inflammation in COVID-19.IMPORTANCE The complex pathogenesis of COVID-19 consists of two major pathological phases: an initial infection phase elicited by SARS-CoV-2 entry and replication and an inflammation phase that could lead to tissue damage, which can evolve into acute respiratory failure or even death. While the development and deployment of vaccines are ongoing, effective therapy for COVID-19 is still urgently needed. In this study, we explored HPSE blockade with Roneparstat, a phase I clinically tested HPSE inhibitor, in the context of COVID-19 pathogenesis. Treatment with Roneparstat showed wide-spectrum anti-infection activities against SARS-CoV-2, HTLV-1, and HIV-1 in vitro. In addition, HPSE blockade with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-induced inflammatory cytokine release from human macrophages through disruption of NF-κB signaling. Together, this study provides a proof of principle for the use of Roneparstat as a dual-targeting therapy for COVID-19 to decrease viral infection and dampen the proinflammatory immune response mediated by macrophages.

The association between neutrophil to lymphocyte ratio and echocardiographic parameters in hospitalised adults with COVID-19 - a retrospective analysis

Funding AcknowledgementsType of funding sources: None.BackgroundThe neutrophil to lymphocyte ratio (NLR) is an inflammatory biomarker with prognostic value in several cardiovascular conditions. Hyperinflammation contributes to severe coronavirus disease 2019 (COVID-19), which is characterized by a multi-organ dysfunction. Cardiovascular complications of COVID-19 include arrhythmias, myocardial damage, acute heart failure, and acute coronary syndrome. Transthoracic echocardiography (TTE) can be used to assess cardiovascular structure and function non-invasively.PurposeTo investigate the association between NLR at admission and TTE abnormalities in hospitalised adults with COVID-19.MethodsThis single-centre retrospective study was conducted at a COVID-19 referral hospital in Indonesia. All consecutive hospitalised adults with confirmed COVID-19 who underwent TTE assessments between 3 April 2020 to 6 April 2021 were included. Comprehensive data including NLR at admission, demographics, co-morbidities, peak severity of COVID-19, and TTE parameters were extracted from electronic medical records. A receiver operating characteristic (ROC) curve analysis was conducted to determine the optimal NLR cut-off for prediction of severe-critical COVID-19. Patients with high and low NLR were compared using the chi-square test and odds ratios (OR), with a confidence level of 95%.ResultsA total of 487 patients were included in this study. From ROC curve analysis, the area under curve was 0.80 (95% CI: 0.76 – 0.84). The optimal NLR cut-off was determined as 4.42, which predicted severe-critical COVID-19 with a sensitivity of 74.5% and a specificity of 74.6%. Based on this, the low NLR and high NLR groups had 223 and 264 patients, respectively. Male sex, diabetes, and chronic kidney disease occurred more frequently in the high NLR group (P < 0.05). On TTE assessment, the high NLR group had higher odds of left ventricular (LV) systolic dysfunction (OR: 2.49; 95% CI: 1.14 – 5.45), LV wall motion abnormalities (OR: 2.62; 95% CI: 1.41 – 4.87), valve abnormalities (OR: 2.04; 95% CI: 1.35 – 3.07), and right ventricular (RV) dysfunction (OR: 10.55; 95% CI: 2.46 – 45.25).ConclusionsCOVID-19 patients with a high NLR at admission had higher odds of abnormal TTE findings, including LV systolic dysfunction, LV wall motion abnormalities, valve abnormalities, and RV dysfunction. This indicates a possible link between inflammation and cardiovascular dysfunction in COVID-19, which must be confirmed in larger prospective studies. Figure. ROC Curve Analysis Figure. Odds Ratios for TTE Abnormalities

Obesity, Inflammation, and Mortality in COVID-19: An Observational Study from the Public Health Care System of New York City.

Severe obesity increases the risk for negative outcomes in patients with coronavirus disease 2019 (COVID-19). Our objectives were to investigate the effect of BMI on in-hospital outcomes in our New York City Health and Hospitals’ ethnically diverse population, further explore this effect by age, sex, race/ethnicity, and timing of admission, and, given the relationship between COVID-19 and hyperinflammation, assess the concentrations of markers of systemic inflammation in different BMI groups. A retrospective study was conducted in hospitalized patients with COVID-19 in the public health care system of New York City from 1 March 2020 to 31 October 2020. A total of 8833 patients were included in this analysis (women: 3593, median age: 62 years). The median body mass index (BMI) was 27.9 kg/m2. Both overweight and obesity were independently associated with in-hospital death. The association of overweight and obesity with death appeared to be stronger in men, younger patients, and individuals of Hispanic ethnicity. We did not observe higher concentrations of inflammatory markers in patients with obesity as compared to those without obesity. In conclusion, overweight and obesity were independently associated with in-hospital death. Obesity was not associated with higher concentrations of inflammatory markers.

Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19.

Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicenter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy. Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plasminogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.

Standardized Extract of Asparagus officinalis Stem Attenuates SARS-CoV-2 Spike Protein-Induced IL-6 and IL-1β Production by Suppressing p44/42 MAPK and Akt Phosphorylation in Murine Primary Macrophages.

Excessive host inflammation following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with severity and mortality in coronavirus disease 2019 (COVID-19). We recently reported that the SARS-CoV-2 spike protein S1 subunit (S1) induces pro-inflammatory responses by activating toll-like receptor 4 (TLR4) signaling in macrophages. A standardized extract of Asparagus officinalis stem (EAS) is a unique functional food that elicits anti-photoaging effects by suppressing pro-inflammatory signaling in hydrogen peroxide and ultraviolet B-exposed skin fibroblasts. To elucidate its potential in preventing excessive inflammation in COVID-19, we examined the effects of EAS on pro-inflammatory responses in S1-stimulated macrophages. Murine peritoneal exudate macrophages were co-treated with EAS and S1. Concentrations and mRNA levels of pro-inflammatory cytokines were assessed using enzyme-linked immunosorbent assay and reverse transcription and real-time polymerase chain reaction, respectively. Expression and phosphorylation levels of signaling proteins were analyzed using western blotting and fluorescence immunomicroscopy. EAS significantly attenuated S1-induced secretion of interleukin (IL)-6 in a concentration-dependent manner without reducing cell viability. EAS also markedly suppressed the S1-induced transcription of IL-6 and IL-1β. However, among the TLR4 signaling proteins, EAS did not affect the degradation of inhibitor κBα, nuclear translocation of nuclear factor-κB p65 subunit, and phosphorylation of c-Jun N-terminal kinase p54 subunit after S1 exposure. In contrast, EAS significantly suppressed S1-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and Akt. Attenuation of S1-induced transcription of IL-6 and IL-1β by the MAPK kinase inhibitor U0126 was greater than that by the Akt inhibitor perifosine, and the effects were potentiated by simultaneous treatment with both inhibitors. These results suggest that EAS attenuates S1-induced IL-6 and IL-1β production by suppressing p44/42 MAPK and Akt signaling in macrophages. Therefore, EAS may be beneficial in regulating excessive inflammation in patients with COVID-19.

Biomarkers of Coagulation and Inflammation in COVID-19-Associated Ischemic Stroke.

[Figure: see text].