SARS-CoV-2 vaccination induced cerebral venous sinus thrombosis: Do megakaryocytes, platelets and lipid mediators make up the orchestra?

The COVID-19 vaccines comprised of adenoviral vectors encoding the Spike (S) glycoprotein of SARS-CoV-2 are highly effective but associated with rare thrombotic complications. The adenovirus vector infects epithelial cells expressing the coxsackievirus and adenovirus receptor (CAR). The S glycoprotein expressed locally stimulates neutralizing antibody and cellular immune responses. These vaccines have been associated with thromboembolic events including cerebral venous sinus thrombosis (CVST). S glycoprotein stimulates the expression of cyclooxygenase-2 (COX-2) and leads to massive generation of thromboxane A2 in COVID-19. Megakaryocytes express CAR and we postulate that S glycoprotein stimulated generation of thromboxane A2 leads to megakaryocyte activation, biogenesis of activated platelets and thereby increased thrombogenicity. Cerebral vein sinuses express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses could be further activated by thromboxane A2-dependent podoplanin-CLEC2 signaling, leading to CVST. A prothrombotic hormonal milieu, and increased generation of thromboxane A2 and platelet activation in healthy females compared to males is consistent with increased risk for CVST observed in women. We propose that antiplatelet agents targeting thromboxane A2 receptor signaling such as low-dose aspirin merit consideration for chemoprophylaxis when administering the adenovirus based COVID-19 vaccines to young adults at risk of thrombosis provided there are no contraindications.

Polysaturated fatty acids and their derivatives regulate respiratory infections.

The regulation of inflammation is a complex pathophysiological process that depends on the production of oxygenated lipid derivatives essential polyunsaturated fatty acids, like omega-3 and omega-6, among which are the lipoxins resolvins and protectins, called specialized pro-resolving lipid mediators (SPM). Their activity is associated with the control of respiratory infection processes to modulate the production of proinflammatory cytokines, avoiding damage due to inflammation-associated necrosis, reducing microbial loads, and promoting tissue remodeling. Therefore, we review some of the biochemical, physiological and immunological aspects of SPM in the regulation of inflammation in respiratory infections.Copyright © 2022, Instituto Nacional de Enfermedades Respiratorias. All rights reserved.

Thrombo-Inflammation in COVID-19 and Sickle Cell Disease: Two Faces of the Same Coin.

People with sickle cell disease (SCD) are at greater risk of severe illness and death from respiratory infections, including COVID-19, than people without SCD (Centers for Disease Control and Prevention, USA). Vaso-occlusive crises (VOC) in SCD and severe SARS-CoV-2 infection are both characterized by thrombo-inflammation mediated by endothelial injury, complement activation, inflammatory lipid storm, platelet activation, platelet-leukocyte adhesion, and activation of the coagulation cascade. Notably, lipid mediators, including thromboxane A2, significantly increase in severe COVID-19 and SCD. In addition, the release of thromboxane A2 from endothelial cells and macrophages stimulates platelets to release microvesicles, which are harbingers of multicellular adhesion and thrombo-inflammation. Currently, there are limited therapeutic strategies targeting platelet-neutrophil activation and thrombo-inflammation in either SCD or COVID-19 during acute crisis. However, due to many similarities between the pathobiology of thrombo-inflammation in SCD and COVID-19, therapies targeting one disease may likely be effective in the other. Therefore, the preclinical and clinical research spurred by the COVID-19 pandemic, including clinical trials of anti-thrombotic agents, are potentially applicable to VOC. Here, we first outline the parallels between SCD and COVID-19; second, review the role of lipid mediators in the pathogenesis of these diseases; and lastly, examine the therapeutic targets and potential treatments for the two diseases.

Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection.

BACKGROUND: SARS-CoV-2 is associated with an increased risk of venous and arterial thrombosis, but the underlying mechanism is still unclear. METHODS: We performed a cross-sectional analysis of platelet function in 25 SARS-CoV-2 and 10 healthy subjects by measuring Nox2 (NADPH oxidase 2)-derived oxidative stress and thromboxane B2, and investigated if administration of monoclonal antibodies against the S protein (Spike protein) of SARS-CoV-2 affects platelet activation. Furthermore, we investigated in vitro if the S protein of SARS-CoV-2 or plasma from SARS-CoV-2 enhanced platelet activation. RESULTS: Ex vivo studies showed enhanced platelet Nox2-derived oxidative stress and thromboxane B2 biosynthesis and under laminar flow platelet-dependent thrombus growth in SARS-CoV-2 compared with controls; both effects were lowered by Nox2 and TLR4 (Toll-like receptor 4) inhibitors. Two hours after administration of monoclonal antibodies, a significant inhibition of platelet activation was observed in patients with SARS-CoV-2 compared with untreated ones. In vitro study showed that S protein per se did not elicit platelet activation but amplified the platelet response to subthreshold concentrations of agonists and functionally interacted with platelet TLR4. A docking simulation analysis suggested that TLR4 binds to S protein via three receptor-binding domains; furthermore, immunoprecipitation and immunofluorescence showed S protein-TLR4 colocalization in platelets from SARS-CoV-2. Plasma from patients with SARS-CoV-2 enhanced platelet activation and Nox2-related oxidative stress, an effect blunted by TNF (tumor necrosis factor) α inhibitor; this effect was recapitulated by an in vitro study documenting that TNFα alone promoted platelet activation and amplified the platelet response to S protein via p47phox (phagocyte oxidase) upregulation. CONCLUSIONS: The study identifies 2 TLR4-dependent and independent pathways promoting platelet-dependent thrombus growth and suggests inhibition of TLR4. or p47phox as a tool to counteract thrombosis in SARS-CoV-2.

Cell specific pro- and antiinflammatory lipidmediator shift in critically ill Covid19 patients

Introduction The COVID-19 pandemic had a significant impact on morbidity and mortality in Germany challenging intensive care unit (ICU) capacities across the country. To delineate the high variability in disease severity, clinical presentation and outcome, we focused on cellular regulators of inflammation and resolution on a single cell level to gain a deeper understanding of the patient's individual inflammatory response and their impact on survival. Methods Written informed consent was obtained from all patients and healthy controls. The study was approved by the local ethical review board (Az249/20 S-EB). To characterize the peripheral immune landscape, we performed a 14 parameter flow cytometric analysis of PBMCs of 32 critically ill CoV2 patients and a targeted HPLC-MS/MS of previously sorted PBMCs. All data was analyzed and correlated to clinical parameters and patients' outcomes (Fig. 4). Results As known [1], computational analysis of flow cytometry revealed a strong decrease of B Cell and CD8+ T Cell ratios and an increase of monocytes in critically ill CoV19 patients compared to control (Fig. 1A). Interestingly, non-survivors displayed an increased ratio of CD16+ monocytes and proinflammatory IL- 1beta in monocytes, B and T cells, while HLADR receptors were downregulated correlating with clinical outcome (Fig. 1B). Not unexpectedly, we saw a major increase in proinflammatory lipidmediators, such as PGJ2, PGF2, TxB2 (Fig. 1C). Additionally, our analysis revealed that not only the amount, but also the source of those mediators was shifted from CD16 to classical CD14 monocytes, even more pronounced in non-survivors. CD16 monocytes of CoV2 patients, however, lost the ability to generate proresolving lipidmediators depending on cytochrome p450 (Cyp450) or soluble epoxide hydrolase (sEH) TxB2 (Fig. 1D). Conclusions Even though a lot of insight into CoV2 has been gained over the last 2 years, relatively little is known about the impact of immune changes in critically ill patients. With this study, we are the first to attribute lipid mediators to specific cell types. Our findings show that TxB2 in critically ill CoV2 patients, which correlates with mortality in CoV2 [2], is produced mainly in CD14 monocytes. We further report that specifically non-survivors display increased ratios of non-classical CD16 monocytes, which are impaired to generate a major class of lipidmediators depending on Cyp450. In conclusion, these data provide evidence that not only the absolute amount of pro- and anti-inflammatory mediators, but also the cellular source of these mediators remains key to fully understand their role in critically ill CoV2 patients. (Figure Presented).

Treatment of COVID-19 Pneumonia and Acute Respiratory Distress With Ramatroban, a Thromboxane A2 and Prostaglandin D2 Receptor Antagonist: A Four-Patient Case Series Report.

Hypoxemia in COVID-19 pneumonia is associated with hospitalization, mechanical ventilation, and mortality. COVID-19 patients exhibit marked increases in fatty acid levels and inflammatory lipid mediators, predominantly arachidonic acid metabolites, notably thromboxane B2 >> prostaglandin E2 > prostaglandin D2. Thromboxane A2 increases pulmonary capillary pressure and microvascular permeability, leading to pulmonary edema, and causes bronchoconstriction contributing to ventilation/perfusion mismatch. Prostaglandin D2-stimulated IL-13 production is associated with respiratory failure, possibly due to hyaluronan accumulation in the lungs. Ramatroban is an orally bioavailable, dual thromboxane A2/TP and prostaglandin D2/DP2 receptor antagonist used in Japan for allergic rhinitis. Four consecutive outpatients with COVID-19 pneumonia treated with ramatroban exhibited rapid relief of dyspnea and hypoxemia within 12-36 h and complete resolution over 5 days, thereby avoiding hospitalization. Therefore, ramatroban as an antivasospastic, broncho-relaxant, antithrombotic, and immunomodulatory agent merits study in randomized clinical trials that might offer hope for a cost-effective pandemic treatment.

Treatment of COVID-19 Pneumonia and Acute Respiratory Distress with Ramatroban, a Thromboxane A2 and Prostaglandin D2 Receptor Antagonist: A 4-Patient Case Series Report

Lungs in COVID-19 patients produce lipid mediators measured in bronchoalveolar lavage fluid (BALF), notably thromboxane B2 (TxB2) >> prostaglandin E2 > prostaglandin D2 (PGD2).1 High levels of TxA2 metabolites in BALF from COVID-19 associated ARDS,1 and systemically in non- ICU COVID-19 patients2,3 led us to propose a critical role for TxA2 prostanoid receptors (TPr) in COVID-19 respiratory distress. We hypothesized that TxA2/TPr signaling in airways, pulmonary microvasculature, and veins contributes to pulmonary edema and hypoxemia in COVID-19 pneumonia. TPr signaling contracts intrapulmonary veins with 10-fold higher potency than arteries.4 High concentrations of TxA2 impede pulmonary venous blood flow, increase microvascular pressure, and force fluid into alveoli.4 TPr signaling also activates platelets and triggers tissue factor expression on monocytes, which may contribute to thrombosis in COVID-19. A TPr antagonist was previously reported to decrease pulmonary capillary pressure by selectively reducing post-capillary resistance in patients with acute lung injury.5 PGD2 stimulation of Dprostanoid receptor 2 (DPr2, aka CRTH2) suppresses interferon lambda (IFN-λ) transcription in the upper respiratory tract in response to respiratory viruses. PGD2/DPr2 antagonism boosts local IFN- λ antiviral responses and limits viral replication.6 Antagonism of TxA2/TPr and PGD2/DPr2 signaling has been proposed for antiviral, antithrombotic and immunomodulatory action in COVID- 19.7 Ramatroban is an oral, dual receptor antagonist of TxA2/TPr and PGD2/DPr2 and a potential candidate for chemoprophylaxis and treatment of COVID-19.1,7 With well-established safety, ramatroban has been used since 2000 in Japan for the treatment of allergic rhinitis.8 We report here a small case series of four consecutive outpatients with COVID-19 with new onset or worsening respiratory distress and hypoxemia who were treated with oral ramatroban (Baynas®, Bayer Yakuhin, Japan). Summarized below, ramatroban afforded rapid improvement in respiratory distress and hypoxemia, followed by complete recovery, successfully avoiding hospitalization. Conclusion: Four consecutive outpatients with COVID-19 were treated with ramatroban. Improvement within hours was followed by gradual complete recovery, thereby avoiding hospitalization. As a safe, oral drug, ramatroban merits clinical trials for both outpatients and hospitalized patients with SARS-CoV-2 infection and COVID-19.

The Lockdown Effect, A1C and Diabetes (LEAD) control audit/study: East London single centre experience

Background: The COVID-19 pandemic resulted in national international implementation of changes to the daily life of individuals. These changes included lockdown and social distancing. During COVID-19 pandemic. During COVID-19,doctors and nurses and other allied healthcare professionals were redeployed to the front line to manage patients presenting with COVID-19 in acute setting. Healthcare providers from different institutions had to adapt to the way of supporting and managing patients with different chronic conditions including diabetes. The implementation of lockdown affected diabetes care (Bonora et al 2020). COVID-19 pandemic enabled healthcare professionals to apply innovation including telemedicine/telephone clinics to manage diabetes patients and other patients needing outpatient follow up. Aim: To assess the effect of lockdown on diabetes control among diabetes patients in East London-Single centre experience. Method: Retrospective cohort study identified patients who were reviewed in the diabetes clinic before and after the pandemic and the A1C levels before December 2019 and in 2021.The data was obtained from clinic letters and clinic notes Demographic data were obtained including type of diabetes mellitus, gender, age. Outcomes assessed were change in HbA1C (worsening or improvement), if the patients had diabetes review during the pandemic (telemedicine) and whether HbA1C blood tests were done. Results: In total the results of HbA1C of 101 patients were identified.46 were females, 55 were males. The patients were aged between 17-to 89 years, mean age 56 years. There was improvement in HbA1c in 26 patients (26%) (despite pandemic and lockdown), and there was deterioration of HbA1c in (74 patient) 74% of all patients. 34 (34%) Patients were type 1 diabetes 61 patients (60%) were type 2 diabetes. 6 patients (6%) were Late Onset Diabetes of Adults (LADA). Discussion: In UK the first lockdown measure prevented spread of prevent spread of COVID-19 was introduced in March 2020.This resulted in disruption of patient‘s care especially those with chronic condition including diabetes. The worsening of diabetes control in these patients is explained by lack of exercise, weight gain and poor diet (Pal et al 2020) and probably poor compliance (Ghosal et al 2020). The patients in this study reported anxiety and stress due uncertainty of COVID-19 pandemic and probably this contributed to worsening HbA1C. HbA1C in 74% of patients in this study deteriorated compared to 26% whose diabetes control improved. COVID-19 pandemic has helped healthcare professional to be more flexible and innovative in managing patients with diabetes and other chronic conditions (Monaghesh,E, Hajizadeh, A 2020).

DESCARTE DE PLASMA RICO EM PLAQUETAS EM RAZÃO DA UTILIZAÇÃO DE FÁRMACOS COM ATIVIDADE ANTIPLAQUETÁRIA NO HEMOCENTRO REGIONAL DE SANTA MARIA DURANTE A PANDEMIA DE COVID-19

Objetivos: Analisar o número de plasma rico em plaquetas desprezados em razão do uso de medicamentos com atividade antiagregante plaquetária no Hemocentro Regional de Santa Maria (HEMOSM) no período da pandemia de COVID-19. Material e métodos: Trata-se de um estudo observacional retrospectivo realizado pela investigação de dados do Sistema HEMOVIDA (Sistema Nacional de Gerenciamento em Serviços de Hemoterapia) no HEMOSM durante o período de fevereiro/2020 a Julho/2021. Resultados: Durante o período da pandemia, foram descartadas 35 bolsas de plasma rico em plaquetas porque os doadores relataram na triagem clínica que haviam feito uso de alguma medicação com atividade antiagregante plaquetária. Discussão: A triagem clínica é uma etapa muito importante na garantia da qualidade dos hemocomponentes porque, através de uma entrevista privada com um profissional da saúde, o doador pode fornecer informações relevantes para que este seja considerado apto ou inapto para a doação. Durante a entrevista, uma das questões postas ao candidato à doação é se este faz ou fez o uso de algum medicamento, isto porque alguns medicamentos podem tornar o doador inapto para a doação de forma permanente (uso contínuo) ou temporariamente, caso o uso do medicamento ocorra de forma esporádica mas tenha antecedido a doação de sangue. A Aspirina®, por exemplo, é um medicamento amplamente difundido, de venda livre e empregado na automedicação. O ácido acetilsalicílico (AAS) é o fármaco (componente ativo) presente na formulação deste medicamento utilizado como analgésico, antitérmico e inclusive (em doses baixas como 75 mg/dia) para evitar eventos trombóticos. A propriedade do AAS que justifica seu uso como profilaxia da trombose é a inibição da síntese de TXA2 plaquetário, e este é justamente o motivo pelo qual doadores que fizeram uso recente do AAS não tem suas plaquetas fracionadas, aproveitando-se apenas o concentrado de hemácias oriundo da doação. A inibição da síntese de TXA2 plaquetário (>95%) implica na deficiência dessas plaquetas em estimular a ativação de novas plaquetas e aumentar a agregação plaquetária, tornando os trombóticos desse doador não funcionais, e, portanto, não efetivos no controle de eventos hemorrágicos quando transfundidos em pacientes plaquetopênicos. O uso de medicamento com atividade antiplaquetários, mesmo não representando um número muito elevado dentre as causas de desprezo de hemocomponentes, representa uma preocupação em relação à automedicação. Ainda, o número de plaquetas randômicas que poderiam ter sido fracionadas destes doadores seria suficiente para atender a aproximadamente 5 prescrições de transfusão de plaquetas (número dependente da quantidade de bolsas solicitadas para a formação do pool de plaquetas randômicas). Conclusão: Considerando o cenário da redução de aproximadamente 10% das doações no HEMOSM e a alta demanda destes hemocomponentes por solicitação dos serviços de saúde atendidos pelo hemocentro, faz-se importante uma orientação mais efetiva para os doadores quanto aos requisitos necessários para a realização da doação e para a garantia da qualidade dos hemocomponentes produzidos.

The effects of acetylsalicylic acid among latino patients of COVID-19

Purpose of Study Retrospective Observational Study. The novel coronavirus SARS-CoV-2, responsible for the Covid-19 pandemic, has led to the death of over 4.8 million people worldwide and over 700 thousand people in the United States. The Latino population has been especially vulnerable and is counted among those most affected by the pandemic. Many fatalities of this novel infection have occurred due to an unknown mechanism causing increased thrombotic activity. Acetylsalicylic Acid (ASA) or aspirin which in low doses functions as an antiplatelet drug by inhibiting thromboxane A2, could be of potential benefit due to its anti-inflammatory and antithrombotic qualities. Methods Used We collected data from the medical charts of 1,039 Latino patients hospitalized to treat COVID-19. We then assessed the outcomes of patients who have been treated with ASA (332) in comparison to those who had not been treated with ASA (707). The main parameter for our study was mortality. Length of hospitalization, ICU admission, and need for supplemental oxygen upon discharge were among the secondary outcomes also analyzed. We investigated further by then selecting for patients who suffered myocardial infarction (MI), stroke, or pneumothorax, and again comparing the two groups. Summary of Results In this study, we found significant evidence that including ASA in COVID-19 treatment regimen decreases the mortality among patients who also suffered a myocardial infarction, stroke, or pneumothorax. These patients were 62% less likely to have a fatality (P=.019) during their stay in the hospital as compared to those who did not receive aspirin. We also found significant evidence suggesting that a treatment regimen including ASA decreased the admission to ICU and the need for oxygen supplementation upon discharge. Patients who were given Aspirin as part of their treatment regimen were 31% less likely of being transferred to the ICU (P=0.036). Patients were also found to be 42% less likely of being discharged with supplemental oxygen if given aspirin as part of their treatment regimen (P=0.003). Conclusions We conclude that our study has shown how aspirin could possibly influence the course of the SARS-CoV-2 viral infection by decreasing thrombotic activity. ASA can have significant health affects among minority populations by improving mortality among patients who also suffered a MI, stroke, or pneumothorax as well as decreasing the strain on hospital ICUs and saving health resources such as oxygen. This important information will be helpful in guiding doctors and other healthcare workers as we continue to battle the COVID-19 pandemic and care for future COVID patients. Further research involving randomized control studies and larger samples sizes must be pursued.

Ramatroban for chemoprophylaxis and treatment of COVID-19: David takes on Goliath.

INTRODUCTION: In COVID-19 pneumonia, there is a massive increase in fatty acid levels and lipid mediators with a predominance of cyclooxygenase metabolites, notably TxB2 ≫ PGE2 > PGD2 in the lungs, and 11-dehydro-TxB2, a TxA2 metabolite, in the systemic circulation. While TxA2 stimulates thromboxane prostanoid (TP) receptors, 11-dehydro-TxB2 is a full agonist of DP2 (formerly known as the CRTh2) receptors for PGD2. Anecdotal experience of using ramatroban, a dual receptor antagonist of the TxA2/TP and PGD2/DP2 receptors, demonstrated rapid symptomatic relief from acute respiratory distress and hypoxemia while avoiding hospitalization. AREAS COVERED: Evidence supporting the role of TxA2/TP receptors and PGD2/DP2 receptors in causing rapidly progressive lung injury associated with hypoxemia, a maladaptive immune response and thromboinflammation is discussed. An innovative perspective on the dual antagonism of TxA2/TP and PGD2/DP2 receptor signaling as a therapeutic approach in COVID-19 is presented. This paper examines ramatroban an anti-platelet, immunomodulator, and antifibrotic agent for acute and long-haul COVID-19. EXPERT OPINION: Ramatroban, a dual blocker of TP and DP2 receptors, has demonstrated efficacy in animal models of respiratory dysfunction, atherosclerosis, thrombosis, and sepsis, as well as preliminary evidence for rapid relief from dyspnea and hypoxemia in COVID-19 pneumonia. Ramatroban merits investigation as a promising antithrombotic and immunomodulatory agent for chemoprophylaxis and treatment.

The Role of Thromboxane in the Course and Treatment of Ischemic Stroke: Review.

Cardiovascular diseases are currently among the leading causes of morbidity and mortality in many developed countries. They are distinguished by chronic and latent development, a course with stages of worsening of symptoms and a period of improvement, and a constant potential threat to life. One of the most important disorders in cardiovascular disease is ischemic stroke. The causes of ischemic stroke can be divided into non-modifiable and modifiable causes. One treatment modality from a neurological point of view is acetylsalicylic acid (ASA), which blocks cyclooxygenase and, thus, thromboxane synthesis. The legitimacy of its administration does not raise any doubts in the case of the acute phase of stroke in patients in whom thrombolytic treatment cannot be initiated. The measurement of thromboxane B2 (TxB2) in serum (a stable metabolic product of TxA2) is the only test that measures the effect of aspirin on the activity of COX-1 in platelets. Measurement of thromboxane B2 may be a potential biomarker of vascular disease risk in patients treated with aspirin. The aim of this study is to present the role of thromboxane B2 in ischemic stroke and to present effective therapies for the treatment of ischemic stroke. Scientific articles from the PubMed database were used for the work, which were selected on the basis of a search for "thromboxane and stroke". Subsequently, a restriction was introduced for works older than 10 years, those concerning animals, and those without full text access. Ultimately, 58 articles were selected. It was shown that a high concentration of TXB2 may be a risk factor for ischemic stroke or ischemic heart disease. However, there is insufficient evidence to suggest that thromboxane could be used in clinical practice as a marker of ischemic stroke. The inclusion of ASA in the prevention of stroke has a beneficial effect that is associated with the effect on thromboxane. However, its insufficient power in 25% or even 50% of the population should be taken into account. An alternative and/or additional therapy could be a selective antagonist of the thromboxane receptor. Thromboxane A2 production is inhibited by estrogen; therefore, the risk of CVD after the menopause and among men is higher. More research is needed in this area.

First Experience Addressing the Prognostic Utility of Novel Urinary Biomarkers in Patients With COVID-19.

Urine 11-dehydro-thromboxane B2 (u11-dh-TxB2), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and liver-type fatty acid binding protein levels (L-FABP) at the time of hospitalization were higher in coronavirus disease 2019 (COVID-19) patients with adverse events vs without events. Higher u11-dh-TxB2 and L-FABP levels were associated with longer hospitalization, more thrombotic events, and greater mortality, providing evidence for potential utility as early prognostic biomarkers for COVID-19.

High levels of eicosanoids and docosanoids in the lungs of intubated COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 is responsible for coronavirus disease 2019 (COVID-19). While COVID-19 is often benign, a subset of patients develops severe multilobar pneumonia that can progress to an acute respiratory distress syndrome. There is no cure for severe COVID-19 and few treatments significantly improved clinical outcome. Dexamethasone and possibly aspirin, which directly/indirectly target the biosynthesis/effects of numerous lipid mediators are among those options. Our objective was to define if severe COVID-19 patients were characterized by increased bioactive lipids modulating lung inflammation. A targeted lipidomic analysis of bronchoalveolar lavages (BALs) by tandem mass spectrometry was done on 25 healthy controls and 33 COVID-19 patients requiring mechanical ventilation. BALs from severe COVID-19 patients were characterized by increased fatty acids and inflammatory lipid mediators. There was a predominance of thromboxane and prostaglandins. Leukotrienes were also increased, notably LTB4 , LTE4 , and eoxin E4 . Monohydroxylated 15-lipoxygenase metabolites derived from linoleate, arachidonate, eicosapentaenoate, and docosahexaenoate were also increased. Finally yet importantly, specialized pro-resolving mediators, notably lipoxin A4 and the D-series resolvins, were also increased, underscoring that the lipid mediator storm occurring in severe COVID-19 involves pro- and anti-inflammatory lipids. Our data unmask the lipid mediator storm occurring in the lungs of patients afflicted with severe COVID-19. We discuss which clinically available drugs could be helpful at modulating the lipidome we observed in the hope of minimizing the deleterious effects of pro-inflammatory lipids and enhancing the effects of anti-inflammatory and/or pro-resolving lipid mediators.

The combination of bromelain and curcumin as an immune-boosting nutraceutical in the prevention of severe COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is still ongoing, while no treatment has been proven effective. COVID-19 pathophysiology involves the activation of three main pathways: the inflammatory, the coagulation and the bradykinin cascades. Here, we highlight for the first time the joint potential therapeutic role of bromelain and curcumin, two well-known nutraceuticals, in the prevention of severe COVID-19. Bromelain (a cysteine protease isolated from the pineapple stem) and curcumin (a natural phenol found in turmeric) exert important immunomodulatory actions interfering in the crucial steps of COVID-19 pathophysiology. Their anti-inflammatory properties include inhibition of transcription factors and subsequent downregulation of proinflammatory mediators. They also present fibrinolytic and anticoagulant properties. Additionally, bromelain inhibits cyclooxygenase and modulates prostaglandins and thromboxane, affecting both inflammation and coagulation, and also hydrolyzes bradykinin. Interestingly, curcumin has been shown in silico studies to prevent entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into cells as well as viral replication, while a recent experimental study has demonstrated that bromelain may also inhibit viral entry into cells. Notably, bromelain substantially increases the absorption of curcumin after oral administration. To the best of our knowledge, this is the first report highlighting the significance of bromelain and, most importantly, the potential preventive value of the synergistic effects of bromelain and curcumin against severe COVID-19.

COVID-19 Sepsis and Microcirculation Dysfunction.

The spreading of Coronavirus (SARS-CoV-2) pandemic, known as COVID-19, has caused a great number of fatalities all around the World. Up to date (2020 May 6) in Italy we had more than 28,000 deaths, while there were more than 205.000 infected. The majority of patients affected by COVID-19 complained only slight symptoms: fatigue, myalgia or cough, but more than 15% of Chinese patients progressed into severe complications, with acute respiratory distress syndrome (ARDS), needing intensive treatment. We tried to summarize data reported in the last months from several Countries, highlighting that COVID-19 was characterized by cytokine storm (CS) and endothelial dysfunction in severely ill patients, where the progression of the disease was fast and fatal. Endothelial dysfunction was the fundamental mechanism triggering a pro-coagulant state, finally evolving into intravascular disseminated coagulation, causing embolization of several organs and consequent multiorgan failure (MOF). The Italian Society of Clinical Hemorheology and Microcirculation was aimed to highlight the role of microcirculatory dysfunction in the pathogenetic mechanisms of COVID-19 during the spreading of the biggest challenges to the World Health.

What about COVID-19 and arachidonic acid pathway?

BACKGROUND AND OBJECTIVE: COVID-19 is a highly contagious viral disease. In this study, we tried to define and discuss all the findings on the potential association between arachidonic acid (AA) pathway and COVID-19 pathophysiology. METHODS: A literature search across PubMed, Scopus, Embase, and Cochrane database was conducted. A total of 25 studies were identified. RESULTS: The data elucidated that COX-2 and prostaglandins (PGs), particularly PGE2, have pro-inflammatory action in COVID-19 pathophysiology. Arachidonic acid can act as endogenous antiviral compound. A deficiency in AA can make humans more susceptible to COVID-19. Targeting these pro-inflammatory mediators may help in decreasing the mortality and morbidity rate in COVID-19 patients. CONCLUSIONS: PGE2 levels and other PGs levels should be measured in patients with COVID-19. Lowering the PGE2 levels through inhibition of human microsomal prostaglandin E synthase-1 (mPGES-1) can enhance the host immune response against COVID-19. In addition, the hybrid compounds, such as COX-2 inhibitors/TP antagonists, can be an innovative treatment to control the overall balance between AA mediators in patients with COVID-19.