Neuropsychiatric Consequences of COVID-19 Pandemic: A Synthetic Review from a Global Perspective.

Some research suggests that distress, secondary to isolation and fear following COVID-19 infection, can negatively affect the long-term more than the COVID-19 infection itself. This narrative review aims to provide a global view on the neuropsychiatric consequences of COVID-19 that can be ascribed to several factors, ranging from the direct effect of infection, to the body's responses against the infection, or to the psychological sequelae of social isolation, unemployment, and fear for one's health and livelihood. Current findings show that the more severe the respiratory infection, the more likely are central nervous system (CNS) complications regarding the infection itself. The immune reactions to the infection may result in symptoms similar to chronic fatigue as well as neurocognitive deficits, which last long after the infection is gone. An increase in symptoms of depression, anxiety, and trauma-related stress may also follow upon economic fears and isolation from friends and family. The consequences of the pandemic are not limited to adults; children learning remotely and away from classmates and routine activities may develop adjustment disorders, acute stress disorder, and a variety of manifestations of grief. A summary of case reports suggests that COVID-19-related stress, economic recession, and political unrest increase the risk of suicidal behaviors and acts of violence. However, it is unknown whether manifestations of mental disorders result from social causes or whether CNS complications may be responsible.

Increased ACE2, sRAGE, and immune activation, but lowered calcium and magnesium in COVID-19.

BACKGROUND: The characterization of new biomarkers that could help to externally validate the diagnosis of COVID-19 and to optimize treatments is extremely important. Many studies established changes in immune-inflammatory and antibody levels, but few studies measured the soluble receptor for advanced glycation end product (sRAGE), angiotensin-converting enzyme 2 (ACE2), calcium and magnesium in COVID-19. OBJECTIVE: To evaluate serum advanced glycation end-product receptor (sRAGE) and angiotensin converting enzyme (ACE)2 and peripheral oxygen saturation (SpO2) and chest CT scan abnormalities (CCTA) in COVID-19. METHODS: sRAGE, ACE2, interleukin (IL)-6, IL-10, C-reactive protein (CRP), calcium, magnesium, and albumin were measured in 60 COVID-19 patients and 30 healthy controls. RESULTS: COVID-19 is characterized by significantly increased IL-6, CRP, IL-10, sRAGE, ACE2, and lowered SpO2, albumin, magnesium and calcium. COVID-19 with CCTAs showed lower SpO2 and albumin. SpO2 was significantly inversely correlated with IL-6, IL-10, CRP, sRAGE, and ACE2, and positively with albumin, magnesium and calcium. Neural networks showed that a combination of calcium, IL-6, CRP, and sRAGE yielded an accuracy of 100% in detecting COVID-19 patients with calcium being the most important predicter followed by IL-6, and CRP. Patients with positive IgG results showed a significant elevation in the serum level of IL-6, sRAGE, and ACE2 compared to the negatively IgG patient subgroup. CONCLUSION: The results show that immune-inflammatory and RAGE pathways biomarkers may be used as external validating criterion for the diagnosis COVID-19. Those pathways coupled with lowered SpO2, calcium and magnesium are drug targets that may help to reduce the consequences of COVID-19.

The cytokine storms of COVID-19, H1N1 influenza, CRS and MAS compared. Can one sized treatment fit all?

An analysis of published data appertaining to the cytokine storms of COVID-19, H1N1 influenza, cytokine release syndrome (CRS), and macrophage activation syndrome (MAS) reveals many common immunological and biochemical abnormalities. These include evidence of a hyperactive coagulation system with elevated D-dimer and ferritin levels, disseminated intravascular coagulopathy (DIC) and microthrombi coupled with an activated and highly permeable vascular endothelium. Common immune abnormalities include progressive hypercytokinemia with elevated levels of TNF-α, interleukin (IL)-6, and IL-1ß, proinflammatory chemokines, activated macrophages and increased levels of nuclear factor kappa beta (NFκB). Inflammasome activation and release of damage associated molecular patterns (DAMPs) is common to COVID-19, H1N1, and MAS but does not appear to be a feature of CRS. Elevated levels of IL-18 are detected in patients with COVID-19 and MAS but have not been reported in patients with H1N1 influenza and CRS. Elevated interferon-γ is common to H1N1, MAS, and CRS but levels of this molecule appear to be depressed in patients with COVID-19. CD4+ T, CD8+ and NK lymphocytes are involved in the pathophysiology of CRS, MAS, and possibly H1N1 but are reduced in number and dysfunctional in COVID-19. Additional elements underpinning the pathophysiology of cytokine storms include Inflammasome activity and DAMPs. Treatment with anakinra may theoretically offer an avenue to positively manipulate the range of biochemical and immune abnormalities reported in COVID-19 and thought to underpin the pathophysiology of cytokine storms beyond those manipulated via the use of, canakinumab, Jak inhibitors or tocilizumab. Thus, despite the relative success of tocilizumab in reducing mortality in COVID-19 patients already on dexamethasone and promising results with Baricitinib, the combination of anakinra in combination with dexamethasone offers the theoretical prospect of further improvements in patient survival. However, there is currently an absence of trial of evidence in favour or contravening this proposition. Accordingly, a large well powered blinded prospective randomised controlled trial (RCT) to test this hypothesis is recommended.

Preventing the development of severe COVID-19 by modifying immunothrombosis.

BACKGROUND: COVID-19-associated acute respiratory distress syndrome (ARDS) is associated with significant morbidity and high levels of mortality. This paper describes the processes involved in the pathophysiology of COVID-19 from the initial infection and subsequent destruction of type II alveolar epithelial cells by SARS-CoV-2 and culminating in the development of ARDS. MAIN BODY: The activation of alveolar cells and alveolar macrophages leads to the release of large quantities of proinflammatory cytokines and chemokines and their translocation into the pulmonary vasculature. The presence of these inflammatory mediators in the vascular compartment leads to the activation of vascular endothelial cells platelets and neutrophils and the subsequent formation of platelet neutrophil complexes. These complexes in concert with activated endothelial cells interact to create a state of immunothrombosis. The consequence of immunothrombosis include hypercoagulation, accelerating inflammation, fibrin deposition, migration of neutrophil extracellular traps (NETs) producing neutrophils into the alveolar apace, activation of the NLRP3 inflammazome, increased alveolar macrophage destruction and massive tissue damage by pyroptosis and necroptosis Therapeutic combinations aimed at ameliorating immunothrombosis and preventing the development of severe COVID-19 are discussed in detail.

Can endolysosomal deacidification and inhibition of autophagy prevent severe COVID-19?

The possibility is examined that immunomodulatory pharmacotherapy may be clinically useful in managing the pandemic coronavirus disease 2019 (COVID-19), known to result from infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded RNA virus. The dominant route of cell entry of the coronavirus is via phagocytosis, with ensconcement in endosomes thereafter proceeding via the endosomal pathway, involving transfer from early (EEs) to late endosomes (LEs) and ultimately into lysosomes via endolysosomal fusion. EE to LE transportation is a rate-limiting step for coronaviruses. Hence inhibition or dysregulation of endosomal trafficking could potentially inhibit SARS-CoV-2 replication. Furthermore, the acidic luminal pH of the endolysosomal system is critical for the activity of numerous pH-sensitive hydrolytic enzymes. Golgi sub-compartments and Golgi-derived secretory vesicles also depend on being mildly acidic for optimal function and structure. Activation of endosomal toll-like receptors by viral RNA can upregulate inflammatory mediators and contribute to a systemic inflammatory cytokine storm, associated with a worsened clinical outcome in COVID-19. Such endosomal toll-like receptors could be inhibited by the use of pharmacological agents which increase endosomal pH, thereby reducing the activity of acid-dependent endosomal proteases required for their activity and/or assembly, leading to suppression of antigen-presenting cell activity, decreased autoantibody secretion, decreased nuclear factor-kappa B activity and decreased pro-inflammatory cytokine production. It is also noteworthy that SARS-CoV-2 inhibits autophagy, predisposing infected cells to apoptosis. It is therefore also suggested that further pharmacological inhibition of autophagy might encourage the apoptotic clearance of SARS-CoV-2-infected cells.

The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach.

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.