Question: What is the mechanism of inflammatory response and pathogenesis of COVID-19 cases?

Title: COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Content: COVID-19, caused by the SARS-CoV-2 virus, has become pandemic. With sharply rising infection rates, patient groups characterized by an enhanced infection risk will be challenged by the virus. In this context, patients with chronic immune-mediated inflammatory diseases are of particular interest, as these diseases are characterized by an intrinsic immune dysfunction leading to inflammation that may enhance risk for severe infection.

Title: A dynamic immune response shapes COVID-19 progression Content: The inflammatory response to SARS-coronavirus-2 (SARS-CoV-2) infection is thought to underpin COVID-19 pathogenesis We conducted daily transcriptomic profiling of three COVID-19 cases and found that the early immune response in COVID-19 patients is highly dynamic Patient throat swabs were tested daily for SARS-CoV-2 with the virus persisting for 3-4 weeks in all three patients Cytokine analyses of whole blood revealed increased cytokine expression in the single more severe case However, most inflammatory gene expression peaked after respiratory function nadir, except those in the IL1 pathway Parallel analyses of CD4 and CD8 expression suggested that the pro-inflammatory response may be intertwined with T-cell activation that could exacerbate disease or prolong the infection Collectively, these findings hint at the possibility that IL1 and related pro-inflammatory pathways may be prognostic and serve as therapeutic targets for COVID-19 This work may also guide future studies to illuminate COVID-19 pathogenesis and develop host-directed therapies

Title: New intriguing possibility for prevention of coronavirus pneumonitis: Natural purified polyphenols Content: COVID-19 is an infectious disease characterized by several important systemic problems such as severe pneumonia. One of mechanisms responsible of these systemic problems is the release of pro-inflammatory cytokines, such as interleukin (IL)-1beta and IL-6(Conti et al., 2020). The binding of virus to TRL (Toll Like Receptor) can determine the release of pro-IL-1beta with successive activation and production of active mature IL-1beta, responsible of lung inflammation, fever and fibrosis(Conti et al., 2020). The interstitial pneumonia is linked to an over-production of IL-6. Based on this principle, several researchers started the use of an anti-arthritis drug, tocilizumab, for its anti-IL-6 action.

Title: COVID-19: Pathogenesis, Genetic Polymorphism, Clinical Features and Laboratory Findings. Content: COVID-19 caused by a novel agent SARS-CoV-2 progressed to a pandemic condition and resulted in a major public health concern worldwide, leading to social and economic issues at the same time. The pathogenesis of COVID-19 starts with the bonding of the virus to ACE-2 receptors expressed in many tissues, and the triggered excessive immune response plays a critical role in the course of the disease. The cytokine storm that occurs upon excessive production of pro-inflammatory cytokines is considered responsible for the severe progression of the disease and the organ damage. However, the accurate pathophysiological mechanism of the disease, which progresses with various clinical presentations, is still substantially unknown. While various studies have been conducted on the effect of genetic polymorphism on the course and severity of the disease, the presence of a significant effect has not been proven yet. The clinical course of the disease is variable, with clinical representation ranging from 81% mild course to 14% severe course along with 5% critical course in patients. Asymptomatic course is considered to be higher than expected, although its frequency is not known exactly. Older adults and those with comorbidities are exposed to a more severe disease course. The disease progress with various symptoms, such as fever, cough, dyspnea, malaise, myalgia, taste and smell dysfunctions, diarrhea, and headache. A range of complications (Acute Respiratory Distress Syndrome, thromboembolic conditions, arrhythmia and cardiac events, secondary infections) could be seen during the course of the disease. Varied laboratory tests are vital to determine the severity and prognosis of the disease, along with the condition and exposure of the affected systems during the course of COVID-19.

Title: COVID-19: pathogenesis, genetic polymorphism, clinical features and laboratory findings Content: COVID-19 caused by a novel agent SARS-CoV-2 progressed to a pandemic condition and resulted in a major public health concern worldwide, leading to social and economic issues at the same time. The pathogenesis of COVID-19 starts with the bonding of the virus to ACE2 receptors expressed in many tissues, and the triggered excessive immune response plays a critical role in the course of the disease. The cytokine storm that occurs upon excessive production of pro-inflammatory cytokines is considered responsible for the severe progression of the disease and the organ damage. However, the accurate pathophysiological mechanism of the disease, which progresses with various clinical presentations, is still substantially unknown. While various studies have been conducted on the effect of genetic polymorphism on the course and severity of the disease, the presence of a significant effect has not been proven yet. The clinical course of the disease is variable, with clinical representation ranging from 81% mild course to 14% severe course along with 5% critical course in patients. Asymptomatic course is considered to be higher than expected, although its frequency is not known exactly. Older adults and those with comorbidities are exposed to a more severe disease course. The disease progress with various symptoms, such as fever, cough, dyspnea, malaise, myalgia, taste and smell dysfunctions, diarrhea, and headache. A range of complications (acute respiratory distress syndrome, thromboembolic conditions, arrhythmia and cardiac events, secondary infections) could be seen during the course of the disease. Varied laboratory tests are vital to determine these verity and prognosis of the disease, along with the condition and exposure of the affected systems during thecourse of COVID-19.

Title: Innate Immune Signaling and Proteolytic Pathways in the Resolution or Exacerbation of SARS-CoV-2 in Covid-19: Key Therapeutic Targets? Content: COVID-19 is caused by the Severe Acute Respiratory Syndrome (SARS) coronavirus (Cov)-2, an enveloped virus with a positive-polarity, single-stranded RNA genome. The initial outbreak of the pandemic began in December 2019, and it is affecting the human health of the global community. In common with previous pandemics (Influenza H1N1 and SARS-CoV) and the epidemics of Middle east respiratory syndrome (MERS)-CoV, CoVs target bronchial and alveolar epithelial cells. Virus protein ligands (e.g., haemagglutinin or trimeric spike glycoprotein for Influenza and CoV, respectively) interact with cellular receptors, such as (depending on the virus) either sialic acids, Dipeptidyl peptidase 4 (DPP4), or angiotensin-converting enzyme 2 (ACE2). Host proteases, e.g., cathepsins, furin, or members of the type II transmembrane serine proteases (TTSP) family, such as Transmembrane protease serine 2 (TMPRSS2), are involved in virus entry by proteolytically activating virus ligands. Also involved are Toll Like Receptor (TLR) family members, which upregulate anti-viral and pro-inflammatory mediators [interleukin (IL)-6 and IL-8 and type I and type III Interferons among others], through the activation of Nuclear Factor (NF)-kB. When these events (virus cellular entry and innate immune responses) are uncontrolled, a deleterious systemic response is sometimes encountered in infected patients, leading to the well-described "cytokine storm" and an ensuing multiple organ failure promoted by a downregulation of dendritic cell, macrophage, and T-cell function. We aim to describe how the lung and systemic host innate immune responses affect survival either positively, through downregulating initial viral load, or negatively, by triggering uncontrolled inflammation. An emphasis will be put on host cellular signaling pathways and proteases involved with a view on tackling these therapeutically.

Title: Innate Immune Signaling and Proteolytic Pathways in the Resolution or Exacerbation of SARS-CoV-2 in Covid-19: Key Therapeutic Targets? Content: COVID-19 is caused by the Severe Acute Respiratory Syndrome (SARS) coronavirus (Cov)-2, an enveloped virus with a positive-polarity, single-stranded RNA genome. The initial outbreak of the pandemic began in December 2019, and it is affecting the human health of the global community. In common with previous pandemics (Influenza H1N1 and SARS-CoV) and the epidemics of Middle east respiratory syndrome (MERS)-CoV, CoVs target bronchial and alveolar epithelial cells. Virus protein ligands (e.g., haemagglutinin or trimeric spike glycoprotein for Influenza and CoV, respectively) interact with cellular receptors, such as (depending on the virus) either sialic acids, Dipeptidyl peptidase 4 (DPP4), or angiotensin-converting enzyme 2 (ACE2). Host proteases, e.g., cathepsins, furin, or members of the type II transmembrane serine proteases (TTSP) family, such as Transmembrane protease serine 2 (TMPRSS2), are involved in virus entry by proteolytically activating virus ligands. Also involved are Toll Like Receptor (TLR) family members, which upregulate anti-viral and pro-inflammatory mediators [interleukin (IL)-6 and IL-8 and type I and type III Interferons among others], through the activation of Nuclear Factor (NF)-kB. When these events (virus cellular entry and innate immune responses) are uncontrolled, a deleterious systemic response is sometimes encountered in infected patients, leading to the well-described “cytokine storm” and an ensuing multiple organ failure promoted by a downregulation of dendritic cell, macrophage, and T-cell function. We aim to describe how the lung and systemic host innate immune responses affect survival either positively, through downregulating initial viral load, or negatively, by triggering uncontrolled inflammation. An emphasis will be put on host cellular signaling pathways and proteases involved with a view on tackling these therapeutically.

Title: COVID-19 Hyperinflammation: What about Neutrophils? Content: COVID-19 is often related to hyperinflammation that drives lung or multiorgan injury. The immunopathological mechanisms that cause excessive inflammation are under investigation and constantly updated. Here, a gene network approach was used on recently published data sets to identify possible COVID-19 inflammatory mechanisms and bioactive genes. First, network analysis of putative SARS-CoV-2 cellular receptors led to the mining of a neutrophil-response signature and relevant inflammatory genes. Second, analysis of RNA-seq data sets of lung cells infected with SARS-CoV-2 revealed that infected cells expressed neutrophil-attracting chemokines. Third, analysis of RNA-seq data sets of bronchoalveolar lavage fluid cells from COVID-19 patients identified upregulation of neutrophil genes and chemokines. Different inflammatory genes mined here, including TNFR, IL-8, CXCR1, CXCR2, ADAM10, GPR84, MME, ANPEP, and LAP3, might be druggable targets in efforts to limit SARS-CoV-2 inflammation in severe clinical cases. The possible role of neutrophils in COVID-19 inflammation needs to be studied further.

Title: Distinct infection process of SARS-CoV-2 in human bronchial epithelial cells line Content: COVID-19, caused by SARS-CoV-2, leads to a series of clinical symptoms of respiratory and pulmonary inflammatory reactions via unknown pathologic mechanisms related to the viral infection process in tracheal or bronchial epithelial cells. Investigation of this viral infection in the human bronchial epithelial cell line (16HBE) suggests that SARS-CoV-2 can enter these cells through interaction between its membrane-localized S protein with the ACE2 molecule on the host cell membrane. Further observation indicates distinct viral replication with a dynamic and moderate increase, whereby viral replication does not lead to a specific cytopathic effect but maintains a continuous release of progeny virions from infected cells. Although mRNA expression of various innate immune signaling molecules is altered in the cells, transcription of IFNα, IFNß and IFNÎ³ is unchanged. Furthermore, expression of some interleukins related to inflammatory reactions, such as IL-6, IL-2 and IL-8, is maintained at low levels, whereas that of interleukins involved in immune regulation is upregulated. Interestingly, IL-22, an interleukin that functions mainly in tissue repair, shows very high expression. Collectively, these data suggest a distinct infection process for this virus in respiratory epithelial cells, which may be linked to its clinicopathological mechanism. This article is protected by copyright. All rights reserved.

Title: Dysregulation of the immune system as a driver of the critical course of the novel coronavirus disease 2019 Content: Novel coronavirus disease-2019 (COVID-19) is a highly contagious respiratory-related disease induced by the newly emerged virus SARS-CoV-2. Given that inflammatory immune cells may induce severe lung injury, the involvement of immune factors in the pathogenesis of the disease cannot be overestimated. It has been demonstrated that coronaviruses (CoVs) have developed mechanisms of immune evasion, making them invisible to the immune system at an early stage of infection. The mechanism relies on inhibition of the anti-viral response of type I interferons (IFNs), which supports uncontrolled viral replication in epithelial cells. There is growing body of evidence that the fatal hyperinflammation ('cytokine storm') responsible for the severe course of COVID-19 is a consequence of massive SARS-CoV-2 replication rather than inappropriate hyperresponsiveness of the immune system. Therefore, a dampened innate anti-viral immune response seems to be the primary cause of the delayed critical cascade of uncontrolled immune events leading to fulminating systemic inflammation. The occurrence of virus transmission even in asymptomatic subjects infected with SARS-CoV-2 clearly strengthens the evidence for a key role of sufficient immune control of viral replication in a subset of cases (e.g. in children, a population with highly effective innate immune responses). Although administration of immunomodulatory therapeutics is recommended under certain conditions in the guidelines of COVID-19 management, controversies regarding treatment protocols in immunocompromised patients infected with SARS-CoV-2 still exist. Extended knowledge of clinicians on the dysregulated immune response, which is a driver of the COVID-19 outcome, may improve both therapeutic protocols and the prognosis of SARS-CoV-2 infected patients.

Title: Dysregulation of the immune system as a driver of the critical course of the novel coronavirus disease 2019. Content: Novel coronavirus disease-2019 (COVID-19) is a highly contagious respiratory-related disease induced by the newly emerged virus SARS-CoV-2. Given that inflammatory immune cells may induce severe lung injury, the involvement of immune factors in the pathogenesis of the disease cannot be overestimated. It has been demonstrated that coronaviruses (CoVs) have developed mechanisms of immune evasion, making them invisible to the immune system at an early stage of infection. The mechanism relies on inhibition of the anti-viral response of type I interferons (IFNs), which supports uncontrolled viral replication in epithelial cells. There is growing body of evidence that the fatal hyperinflammation ('cytokine storm') responsible for the severe course of COVID-19 is a consequence of massive SARS-CoV-2 replication rather than inappropriate hyperresponsiveness of the immune system. Therefore, a dampened innate anti-viral immune response seems to be the primary cause of the delayed critical cascade of uncontrolled immune events leading to fulminating systemic inflammation. The occurrence of virus transmission even in asymptomatic subjects infected with SARS-CoV-2 clearly strengthens the evidence for a key role of sufficient immune control of viral replication in a subset of cases (e.g. in children, a population with highly effective innate immune responses). Although administration of immunomodulatory therapeutics is recommended under certain conditions in the guidelines of COVID-19 management, controversies regarding treatment protocols in immunocompromised patients infected with SARS-CoV-2 still exist. Extended knowledge of clinicians on the dysregulated immune response, which is a driver of the COVID-19 outcome, may improve both therapeutic protocols and the prognosis of SARS-CoV-2 infected patients.

Title: Type 3 hypersensitivity in COVID-19 vasculitis Content: Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden, globally. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels.

Title: Type 3 hypersensitivity in COVID-19 vasculitis Content: Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden around the world. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels.

Title: COVID-19 revisiting inflammatory pathways of arthritis Content: Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures. The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis. Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1ß or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19. Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process. COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic. Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19.

Title: Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by COVID-19: anti-inflammatory strategies Content: COVID-19 (coronavirus disease-19) involves humans as well as animals and may cause serious damage to the respiratory tract including the lung This pathogenic virus has been identified in swabs performed on the throat and nose of patients who suffer from or are suspected of the disease When COVID-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1b and IL-6 The binding of COVID-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1b which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1b which is a mediator of lung inflammation, fever and fibrosis Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections Cytokine IL-37 has the ability to suppress innate and acquired immune response and also has the capacity to inhibit inflammation by acting on IL-18Ra receptor IL-37 performs its immunosuppressive activity by acting on mTOR and increasing the adenosine monophosphate (AMP) kinase This cytokine inhibits class II histocompatibility complex (MHC) molecules and inflammation in inflammatory diseases by suppressing MyD88 and subsequently IL-1β, IL-6, TNF and CCL2 The suppression of IL-1b by IL-37 in inflammatory state induced by COVID-19 can have a new therapeutic effect previously unknown Another inhibitory cytokine is IL-38, the newest cytokine of the IL-1 family members, produced by several immune cells including B cells and macrophages IL-38 is also a suppressor cytokine which inhibits IL-1b and other pro-inflammatory IL-family members IL-38 is a potential therapeutic cytokine which inhibits inflammation in viral infections including that caused by COVID-19, providing a new relevant strategy

Title: COVID-19 revisiting inflammatory pathways of arthritis Content: Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures. The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis. Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1β or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19. Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process. COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic. Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19.

Title: A Dynamic Immune Response Shapes COVID-19 Progression Content: The inflammatory response to SARS-coronavirus-2 (SARS-CoV-2) infection is thought to underpin COVID-19 pathogenesis. We conducted daily transcriptomic profiling of three COVID-19 cases and found that the early immune response in COVID-19 patients is highly dynamic. Patient throat swabs were tested daily for SARS-CoV-2, with the virus persisting for 3 to 4 weeks in all three patients. Cytokine analyses of whole blood revealed increased cytokine expression in the single most severe case. However, most inflammatory gene expression peaked after respiratory function nadir, except expression in the IL1 pathway. Parallel analyses of CD4 and CD8 expression suggested that the pro-inflammatory response may be intertwined with T cell activation that could exacerbate disease or prolong the infection. Collectively, these findings hint at the possibility that IL1 and related pro-inflammatory pathways may be prognostic and serve as therapeutic targets for COVID-19. This work may also guide future studies to illuminate COVID-19 pathogenesis and develop host-directed therapies.

Title: Immunological and inflammatory profiles in mild and severe cases of COVID-19 Content: COVID-19 is associated with 5.1% mortality. Although the virological, epidemiological, clinical, and management outcome features of COVID-19 patients have been defined rapidly, the inflammatory and immune profiles require definition as they influence pathogenesis and clinical expression of COVID-19. Here we show lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and NK cells, excessive T-cell activation and high expression of T-cell inhibitory molecules are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules. Histochemical studies of lung tissue from one fatality show sub-anatomical distributions of SARS-CoV-2 RNA and massive infiltration of T cells and macrophages. Thus, aberrant activation and dysregulation of CD8+ T cells occur in patients with severe COVID-19 disease, an effect that might be for pathogenesis of SARS-CoV-2 infection and indicate that immune-based targets for therapeutic interventions constitute a promising treatment for severe COVID-19 patients.

Title: Considerations for Statin Therapy in Patients with COVID‐19 Content: Current coronavirus pandemic named coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is the third coronavirus outbreak during the current century after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses.1 Acute respiratory distress syndrome (ARDS) is an immunopathologic event and main cause of death following COVID-19. The main mechanism of ARDS is uncontrolled systemic inflammatory response and cytokine storm following release of proinflammatory cytokines (such as interferons (IFN), interleukines (IL), tumor necrosis factor (TNF)-α) and chemokines.2-3 So, some Chinese researchers proposed or used anti-inflammatory agents in the treatment regimen of patients with COVID-19.3-4.

Title: Complex Immune Dysregulation in Covid-19 Patients with Severe Respiratory Failure Content: Proper management of COVID-19 mandates better understanding of disease pathogenesis The sudden clinical deterioration 7-8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF All SRF patients displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen (HLA)-DR expression accompanied by profound depletion of CD4-lymphocytes, CD19- lymphocytes and natural killer cells TNFα and IL-6 production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab;off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation

Title: A contemporary review on pathogenesis and immunity of COVID-19 infection Content: Emerging of the COVID-19 pandemic has raised interests in the field of biology and pathogenesis of coronaviruses; including interactions between host immune reactions specific, and viral factors. Deep knowledge about the interaction between coronaviruses and the host factors could be useful to provide a better support for the disease sufferers and be advantageous for managing and treatment of the lung infection caused by the virus. At this study, we reviewed the updated information on the pathogenesis of the COVID-19 and the immune responses toward it, with a special focus on structure, genetics, and viral accessory proteins, viral replication, viral receptors, the human immune reactions, cytopathic effects, and host-related factors.

Title: SARS-CoV2 may evade innate immune response, causing uncontrolled neutrophil extracellular traps formation and multi-organ failure Content: We demonstrate that the general clinical conditions, risk factors and numerous pathological and biological features of COVID-19 are analogous with various disorders caused by the uncontrolled formation of neutrophil extracellular traps and their by-products. Given the rapid evolution of this disease's symptoms and its lethality, we hypothesize that SARS-CoV2 evades innate immune response causing COVID-19 progresses under just such an amplifier loop, leading to a massive, uncontrolled inflammation process. This work allows us to propose new strategies for treating the pandemic.

Title: SARS-CoV2 may evade innate immune response, causing uncontrolled neutrophil extracellular traps formation and multi-organ failure. Content: We demonstrate that the general clinical conditions, risk factors and numerous pathological and biological features of COVID-19 are analogous with various disorders caused by the uncontrolled formation of neutrophil extracellular traps and their by-products. Given the rapid evolution of this disease's symptoms and its lethality, we hypothesize that SARS-CoV2 evades innate immune response causing COVID-19 progresses under just such an amplifier loop, leading to a massive, uncontrolled inflammation process. This work allows us to propose new strategies for treating the pandemic.

Title: COVID-19 : physiopathologie d'une maladie à plusieurs visages./ [COVID-19: Pathogenesis of a multi-faceted disease] Content: SARS-CoV-2 infection, named COVID-19, can lead to a dysregulated immune response and abnormal coagulation responsible for a viral sepsis. In this review, we specify physiopathological mechanisms of each phase of COVID-19 - viral, immune and pro-thrombotic - notably because they involve different treatment. Finally, we specify the physiopathological mechanisms of organ injury.

Title: Lessons from dermatology about inflammatory responses in Covid-19 Content: The SARS-Cov-2 is a single-stranded RNA virus composed of 16 non-structural proteins (NSP 1-16) with specific roles in the replication of coronaviruses. NSP3 has the property to block host innate immune response and to promote cytokine expression. NSP5 can inhibit interferon (IFN) signalling and NSP16 prevents MAD5 recognition, depressing the innate immunity. Dendritic cells, monocytes, and macrophages are the first cell lineage against viruses' infections. The IFN type I is the danger signal for the human body during this clinical setting. Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. In Covid-19 the pathogenesis is not yet fully understood, but viral and host factors seem to play a key role. Important points in severe Covid-19 are characterized by an upregulated innate immune response, hypercoagulopathy state, pulmonary tissue damage, neurological and/or gastrointestinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a 'cytokine storm'. These systemic conditions share polymorphous cutaneous lesions where innate immune system is involved in the histopathological findings with acute respiratory distress syndrome, hypercoagulability, hyperferritinemia, increased serum levels of D-dimer, lactic dehydrogenase, reactive-C-protein and serum A amyloid. It is described that several polymorphous cutaneous lesions similar to erythema pernio, urticarial rashes, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicles lesions, and purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema. This review describes the complexity of Covid-19, its pathophysiological and clinical aspects.

Title: Lessons from dermatology about inflammatory responses in Covid-19. Content: The SARS-Cov-2 is a single-stranded RNA virus composed of 16 non-structural proteins (NSP 1-16) with specific roles in the replication of coronaviruses. NSP3 has the property to block host innate immune response and to promote cytokine expression. NSP5 can inhibit interferon (IFN) signalling and NSP16 prevents MAD5 recognition, depressing the innate immunity. Dendritic cells, monocytes, and macrophages are the first cell lineage against viruses' infections. The IFN type I is the danger signal for the human body during this clinical setting. Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. In Covid-19 the pathogenesis is not yet fully understood, but viral and host factors seem to play a key role. Important points in severe Covid-19 are characterized by an upregulated innate immune response, hypercoagulopathy state, pulmonary tissue damage, neurological and/or gastrointestinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a 'cytokine storm'. These systemic conditions share polymorphous cutaneous lesions where innate immune system is involved in the histopathological findings with acute respiratory distress syndrome, hypercoagulability, hyperferritinemia, increased serum levels of D-dimer, lactic dehydrogenase, reactive-C-protein and serum A amyloid. It is described that several polymorphous cutaneous lesions similar to erythema pernio, urticarial rashes, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicles lesions, and purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema. This review describes the complexity of Covid-19, its pathophysiological and clinical aspects.

Title: COVID-19: laboratory diagnosis for clinicians. An updating article Content: COVID-19 (coronavirus disease 2019) is an infectious disease caused by the new coronavirus associated with severe acute respiratory syndrome 2 (SARS-CoV-2) Coronaviridae comprises a large family, of which at least seven members are known to cause respiratory diseases in humans Coronaviruses have the ability to infect virtually all major groups of animals and, eventually, can infect humans SARS-CoV-2 is the third coronavirus to cross the species barrier and infect humans This virus was identified in an outbreak of pneumonia cases in Wuhan city, Hubei province, China, in December 2019 Its entire genome is inscribed on a single strand of ribonucleic acid Some proteins present on the surface of the virus act as facilitators for its entry into host cells, while others, apparently, are related to its pathogenesis Coronaviruses are responsible for respiratory infections in humans and some animals The infection is often mild to moderate in intensity, but some coronaviruses may cause serious illnesses, such as severe acute respiratory syndrome (SARS), which occurred in 2002, and the Middle East respiratory syndrome (MERS) Coronaviruses can activate an excessive and unregulated immune response, which may promote SARS development Although the lungs are one of the target organs, the hypoxia mechanism is systemic and other organs begin to suffer both through lack of oxygen and through deregulation of inflammation control mechanisms

Title: Early Insights into Immune Responses during COVID-19 Content: Coronavirus disease-2019 (COVID-19) is caused by the newly emerged virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was recently declared as a pandemic by the World Health Organization. In its severe form, the disease is characterized by acute respiratory distress syndrome, and there are no targeted intervention strategies to treat or prevent it. The immune response is thought to both contribute to the pathogenesis of disease and provide protection during its resolution. Thus, understanding the immune response to SARS-CoV-2 is of the utmost importance for developing and testing vaccines and therapeutics. In this review, we discuss the earliest knowledge and hypotheses of the mechanisms of immune pathology in the lung during acute infection as well at the later stages of disease resolution, recovery, and immune memory formation.

Title: Early Insights into Immune Responses during COVID-19. Content: Coronavirus disease-2019 (COVID-19) is caused by the newly emerged virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was recently declared as a pandemic by the World Health Organization. In its severe form, the disease is characterized by acute respiratory distress syndrome, and there are no targeted intervention strategies to treat or prevent it. The immune response is thought to both contribute to the pathogenesis of disease and provide protection during its resolution. Thus, understanding the immune response to SARS-CoV-2 is of the utmost importance for developing and testing vaccines and therapeutics. In this review, we discuss the earliest knowledge and hypotheses of the mechanisms of immune pathology in the lung during acute infection as well at the later stages of disease resolution, recovery, and immune memory formation.

Title: Predicting COVID-19 distribution in Mexico through a discrete and time-dependent Markov chain and an SIR-like model Content: COVID-19 is an emergent viral infection which rose in December 2019 in a city in the Chinese province of Hubei, Wuhan; the viral aetiology of this infection is now known as COVID-19 virus, which belongs to the Betacoronavirus genus. This virus produces the syndrome of acute respiratory stress that h as been witnessed in other coronaviruses, such as that MERS-CoV in Middle East countries or SARS-CoV which was seen in 2002 and 2003 in China. This virus mediates its entry through its spike (S) proteins interacting with ACE2 receptors in lung epithelial cells, and may promote an inflammatory response by means of inflammasome NLRP3 activation and unfolded protein response (these are possibly consequence of the envelope E protein of COVID-19 virus). Efforts have been made worldwide to prevent further spread of the disease, but in March 2020 the WHO declared it a pandemic emergency and Mexico started to report its first cases. In this paper we attempt to summarize the biological features of the virus and the possible pathophysiological mechanisms of its disease, as well as a stochastic model characterizing the probability distribution of cases in Mexico by states and the estimated number of cases in Mexico through a differential equation model (modified SIR model), thus will we be able to characterize the disease and its course in Mexico in order to display more preparedness and promote more logical actions by both the policy makers as well as the general population.

Title: Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure Content: Summary Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7–8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation.

Title: [From SARS to COVID-19: pathogens, receptor, pathogenesis and principles of the treatment] Content: COVID-19 is an infectious disease caused by 2019-nCoV and characterizes as an atypical pneumonia. Since 2019-nCoV is a newly emerging virus, the pathogenesis of COVID-19 is not well known. Most patients had a self-limited course, and some became severe even death. In this review, the authors compared two coronavirus outbreaks during the past two decades: the SARS-CoV and 2019-nCoV. Among the biological nature of the pathogens, viral receptor distribution on the human cells, and the pathological findings in the targeted organs and clinical features of the patients with the diseases, found similarities and differences between the two diseases had been found. Due to the shared receptor ACE2 and the pathological similarities of the SARS-CoV and 2019-nCoV diseases,authors proposed a pathogenesis model for COVID-19. Like the SARS-CoV disease, COVID-19 is a systematic disease and targets the lungs, vasculatures, and the immune system. The basic pathogenesis involves two interlinked processes: a severe lung inflammation and immune deficiency, both of which were related to an inappropriate immune response and over-production of cytokines. Thus, treatment approaches should include antiviral and anti-proinflammatory cytokines, anti-infectious and life support therapies, especially in patients with severe diseases.

Title: Cytokine Storm in COVID19: A Neural Hypothesis Content: Cytokine storm in COVID-19 is characterized by an excessive inflammatory response to SARS-CoV-2 that is caused by a dysregulated immune system of the host. We are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of nucleus tractus solitarius (NTS) may be responsible for the cytokine storm in COVID 19. The inflamed NTS may result in a dysregulated cholinergic anti-inflammatory pathway and hypothalamic-pituitary-adrenal axis.

Title: Cytokine Storm in COVID19: A Neural Hypothesis. Content: Cytokine storm in COVID-19 is characterized by an excessive inflammatory response to SARS-CoV-2 that is caused by a dysregulated immune system of the host. We are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of nucleus tractus solitarius (NTS) may be responsible for the cytokine storm in COVID 19. The inflamed NTS may result in a dysregulated cholinergic anti-inflammatory pathway and hypothalamic-pituitary-adrenal axis.

Title: Severe COVID-19, Another Piece in the Puzzle of the Hyperferritinemic Syndrome. An Immunomodulatory Perspective to Alleviate the Storm Content: The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the "hyperferritinemic syndrome" category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies.

Title: SnapShot: COVID-19 Content: Abstract Coronavirus disease 2019 (COVID-19) is a novel respiratory illness caused by SARS-CoV-2. Viral entry is mediated through viral spike protein and host ACE2 enzyme interaction. Most cases are mild; severe disease often involves cytokine storm and organ failure. Therapeutics including antivirals, immunomodulators, and vaccines are in development. To view this SnapShot, open or download the PDF.

Title: What would Sérgio Ferreira say to your physician in this war against COVID-19: How about kallikrein/kinin system? Content: Coronavirus disease 2019 (COVID-19) is an infectious disease with fast spreading all over the world caused by the SARS-CoV-2 virus which can culminate in a severe acute respiratory syndrome by the injury caused in the lungs. However, other organs can be also damaged. SARS-CoV-2 enter into the host cells using the angiotensin-converting enzyme 2 (ACE2) as receptor, like its ancestor SARS-CoV. ACE2 is then downregulated in lung tissues with augmented serum levels of ACE2 in SARS-CoV-2 patients. Interestingly, ACE2+ organs reveal the symptomatic repercussions, which are signals of the infection such as dry cough, shortness of breath, heart failure, liver and kidney damage, anosmia or hyposmia, and diarrhea. ACE2 exerts a chief role in the renin-angiotensin system (RAS) by converting angiotensin II to angiotensin-(1-7) that activates Mas receptor, inhibits ACE1, and modulates bradykinin (BK) receptor sensitivity, especially the BK type 2 receptor (BKB2R). ACE2 also hydrolizes des-Arg9-bradykinin (DABK), an active BK metabolite, agonist at BK type 1 receptors (BKB1R), which is upregulated by inflammation. In this opinion article, we conjecture a dialogue by the figure of Sérgio Ferreira which brought together basic science of classical pharmacology and clinical repercussions in COVID-19, then we propose that in the course of SARS-CoV-2 infection: i) downregulation of ACE2 impairs the angiotensin II and DABK inactivation; ii) BK and its metabolite DABK seems to be in elevated levels in tissues by interferences in kallikrein/kinin system; iii) BK1 receptor contributes to the outbreak and maintenance of the inflammatory response; iv) kallikrein/kinin system crosstalks to RAS and coagulation system, linking inflammation to thrombosis and organ injury. We hypothesize that targeting the kallikrein/kinin system and BKB1R pathway may be beneficial in SARS-CoV-2 infection, especially on early stages. This route of inference should be experimentally verified by SARS-CoV-2 infected mice.

Title: What would sérgio ferreira say to your physician in this war against COVID-19: How about kallikrein/kinin system? Content: Coronavirus disease 2019 (COVID-19) is an infectious disease with fast spreading all over the world caused by the SARS-CoV-2 virus which can culminate in a severe acute respiratory syndrome by the injury caused in the lungs. However, other organs can be also damaged. SARS-CoV-2 enter into the host cells using the angiotensin-converting enzyme 2 (ACE2) as receptor, like its ancestor SARS-CoV. ACE2 is then downregulated in lung tissues with augmented serum levels of ACE2 in SARS-CoV-2 patients. Interestingly, ACE2(+) organs reveal the symptomatic repercussions, which are signals of the infection such as dry cough, shortness of breath, heart failure, liver and kidney damage, anosmia or hyposmia, and diarrhea. ACE2 exerts a chief role in the renin-angiotensin system (RAS) by converting angiotensin II to angiotensin-(1-7) that activates Mas receptor, inhibits ACE1, and modulates bradykinin (BK) receptor sensitivity, especially the BK type 2 receptor (BKB2R). ACE2 also hydrolizes des-Arg(9)-bradykinin (DABK), an active BK metabolite, agonist at BK type 1 receptors (BKB1R), which is upregulated by inflammation. In this opinion article, we conjecture a dialogue by the figure of Sérgio Ferreira which brought together basic science of classical pharmacology and clinical repercussions in COVID-19, then we propose that in the course of SARS-CoV-2 infection: i) downregulation of ACE2 impairs the angiotensin II and DABK inactivation; ii) BK and its metabolite DABK seems to be in elevated levels in tissues by interferences in kallikrein/kinin system; iii) BK1 receptor contributes to the outbreak and maintenance of the inflammatory response; iv) kallikrein/kinin system crosstalks to RAS and coagulation system, linking inflammation to thrombosis and organ injury. We hypothesize that targeting the kallikrein/kinin system and BKB1R pathway may be beneficial in SARS-CoV-2 infection, especially on early stages. This route of inference should be experimentally verified by SARS-CoV-2 infected mice.

Title: SnapShot: COVID-19 Content: Coronavirus disease 2019 (COVID-19) is a novel respiratory illness caused by SARS-CoV-2. Viral entry is mediated through viral spike protein and host ACE2 enzyme interaction. Most cases are mild; severe disease often involves cytokine storm and organ failure. Therapeutics including antivirals, immunomodulators, and vaccines are in development. To view this SnapShot, open or download the PDF.

Title: Potential mechanisms of cardiac injury and common pathways of inflammation in patients with COVID-19 Content: Due to the lack of prospective, randomized, controlled clinical studies on inflammation and cardiovascular involvement, the exact mechanism of cardiac injury among patients with COVID-19 still remains uncertain. It was demonstrated that there is a high and significantly positive linear correlation between troponin T and plasma high-sensitivity C-reactive protein levels, biomarkers of cardiac injury and systemic inflammation, respectively. Cardiac injury and inflammation is a relatively common association among patients hospitalized with COVID-19, and it is related to higher risk of in-hospital mortality. In our literature search, we identified several potential mechanisms of myocardial tissue damage, namely, coronavirus-associated acute myocarditis, angiotensin-converting enzyme 2 receptor binding affinity to the virus Spike protein, increased cytokine secretion, and hypoxia induced cardiac myocyte apoptosis. Elucidation of the disease pathogenesis and prospective histopathological studies are crucial for future proper treatment in case of renewed outbreaks. Of interest is that with hundred of thousands of bodies available for autopsy studies, no prospective investigation has been reported so far. Strong efforts and continued research of the cardiovascular complications and identification of risk factors for poor prognosis in COVID-19 are steadily needed. The high morbidity and mortality of COVID-19, its monumental economic burden and social impact, the despair of a new pandemic outbreak, and the thread of potential utilization of novel SARS-CoV2 as biologic weapons make it a preponderant necessity to better comprehend the therapeutic management of this lethal disease. Emerging as an acute infectious disease, COVID-19 may become a chronic epidemic because of genetic recombination. Therefore, we should be ready for the reemergence of COVID-19 or other coronaviruses.

Title: [From SARS to COVID-19: pathogens, receptor, pathogenesis and principles of the treatment]. Content: COVID-19 is an infectious disease caused by 2019-nCoV and characterizes as an atypical pneumonia. Since 2019-nCoV is a newly emerging virus, the pathogenesis of COVID-19 is not well known. Most patients had a self-limited course, and some became severe even death. In this review, the authors compared two coronavirus outbreaks during the past two decades: the SARS-CoV and 2019-nCoV. Among the biological nature of the pathogens, viral receptor distribution on the human cells, and the pathological findings in the targeted organs and clinical features of the patients with the diseases, found similarities and differences between the two diseases. Due to the shared receptor ACE2 and the pathological similarities of the SARS-CoV and 2019-nCoV diseases. They proposed a pathogenesis model for COVID-19. Like the SARS-CoV disease, COVID-19 is a systematic disease and targets the lungs, vasculatures, and the immune system. The basic pathogenesis involves two interlinked processes: a severe lung inflammation and immune deficiency, both of which are related to an inappropriate immune response and over-production of cytokines. Thus, treatment approaches should include antiviral and anti-proinflammatory cytokines, anti-infectious and life support therapies, especially in patients with severe diseases.

Title: IL-6 blockade treatment for severe COVID-19 in two patients with multiple myeloma. Content: Coronavirus disease 2019 (COVID-19) presents with a broad clinical spectrum, varying from asymptomatic infection to severe pneumonitis, leading to acute respiratory distress syndrome (ARDS) and death(Guan, et al 2020). Accumulating evidence suggests that in severe COVID-19, an acute hyperinflammatory syndrome characterised by fever, hypoxia and increased serum inflammatory markers, occurring 5-10 days from the first symptoms, is the major driver of morbidity and death(Zhou, et al 2020b). Hyperinflammation is not specific to COVID-19. Similar syndromes were previously described in respiratory disease associated with other coronaviruses, including the severe acute respiratory syndrome-coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome-coronavirus (MERS-CoV) in 2012(Castilletti, et al 2005, Tseng, et al 2005).

Title: Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies Content: Coronavirus-19 (COVI-19) involves humans as well as animals and may cause serious damage to the respiratory tract, including the lung: coronavirus disease (COVID-19). This pathogenic virus has been identified in swabs performed on the throat and nose of patients who suffer from or are suspected of the disease. When COVI-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1ß and IL-6. The binding of COVI-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1ß which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1ß which is a mediator of lung inflammation, fever and fibrosis. Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. Cytokine IL-37 has the ability to suppress innate and acquired immune response and also has the capacity to inhibit inflammation by acting on IL-18Rα receptor. IL-37 performs its immunosuppressive activity by acting on mTOR and increasing the adenosine monophosphate (AMP) kinase. This cytokine inhibits class II histocompatibility complex (MHC) molecules and inflammation in inflammatory diseases by suppressing MyD88 and subsequently IL-1ß, IL-6, TNF and CCL2. The suppression of IL-1ß by IL-37 in inflammatory state induced by coronavirus-19 can have a new therapeutic effect previously unknown. Another inhibitory cytokine is IL-38, the newest cytokine of the IL-1 family members, produced by several immune cells including B cells and macrophages. IL-38 is also a suppressor cytokine which inhibits IL-1ß and other pro-inflammatory IL-family members. IL-38 is a potential therapeutic cytokine which inhibits inflammation in viral infections including that caused by coronavirus-19, providing a new relevant strategy.

Title: Severe COVID-19, Another Piece in the Puzzle of the Hyperferritinemic Syndrome. An Immunomodulatory Perspective to Alleviate the Storm Content: The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the “hyperferritinemic syndrome” category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies.

Title: Mechanisms of Myocardial Injury in Coronavirus Disease 2019 Content: Coronavirus disease 2019 (COVID-19) predominantly presents with symptoms of fever, fatigue, cough and respiratory failure. However, it appears to have a unique interplay with cardiovascular disease (CVD); patients with pre-existing CVD are at highest risk for mortality from COVID-19, along with the elderly. COVID-19 contributes to cardiovascular complications including arrhythmias, myocardial dysfunction and myocardial inflammation. Although the exact mechanism of myocardial inflammation in patients with COVID-19 is not known, several plausible mechanisms have been proposed based on early observational reports. In this article, the authors summarise the available literature on mechanisms of myocardial injury in COVID-19.

Title: Potential pathophysiological mechanisms leading to increased COVID-19 susceptibility and severity in obesity Content: As we are facing worldwide pandemic of COVID-19, we aimed to identify potential pathophysiological mechanisms leading to increased COVID-19 susceptibility and severity in obesity. Special emphasis will be given on increased susceptibility to infections due to obesity-related low-grade chronic inflammation, higher expression of angiotensin converting enzyme-2 and pathway-associated components, as well as decreased vitamin D bioavailability, since all of them provide easier ways for the virus to enter into host cells, replicate and stunt adequate immune responses.

Title: Unraveling the mystery of Covid-19 cytokine storm: From skin to organ systems Content: COVID-19 is a global pandemic that emerged from Wuhan, China. Besides pneumonia and acute respiratory distress syndrome, the disease leads to multisystem involvement in the form of myocarditis, arrhythmias, cardiac arrest, gastrointestinal symptoms, hypoxemic brain injury, acute liver, and renal function impairment. There are also reports of cutaneous lesions in form of urticarial and maculopapular rashes, chilblain like fingers and toes (covid feet), livedoid vasculopathy, and chicken-pox like or varicelliform vesicles. Clinically, many of these skin lesions are likely secondary to occlusion of small to medium blood vessels due to microthrombi formation or due to viral laden antigen-antibody immune complexes; and same explanation may hold true for possible hypoxemic injury simultaneously occurring in other vital organs like lungs, heart, brain, and kidneys. The histopathology, immunoflorescence and RT-PCR analysis of skin biopsies can provide useful insights for ascertaining the pathogenesis of this complex viral syndrome. Apparently, it is interplay of disarmed cellular immunity and over-activated humoral immunity that culminates in end-organ changes. The morbidity and mortality can be significantly reduced by upgrading the cellular immunity and downgrading the humoral response; along with prevention of hypoxemic and reperfusion injuries by using antivirals, immunomodulators, antioxidants, anti-platelets, and anticoagulants in judicious and phased manner.

Title: SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression Content: Since the WHO declared COVID-19 a pandemic, a great effort has been made to understand this serious disease. Thousands of studies are being devoted to understanding its epidemiology, its molecular characteristics, its mechanisms, and the clinical evolution of this viral infection. However, little has been published on its pathogenesis and the host response mechanisms in the progress of the disease. Therefore, we propose a hypothesis based on strong scientific documentation, associating oxidative stress with changes found in patients with COVID-19, such as its participation in the amplification and perpetuation of the cytokine storm, coagulopathy, and cell hypoxia. Finally, we suggest a therapeutic strategy to reduce oxidative stress using antioxidants, NFkB inhibitors, Nrf2 activators, and iron complexing agents. We believe that this hypothesis can guide new studies and therapeutic strategies on this topic.

Title: COVID-19 and the immune system Content: A close interaction between the virus SARS-CoV-2 and the immune system of an individual results in a diverse clinical manifestation of the COVID-19 disease While adaptive immune responses are essential for SARS-CoV-2 virus clearance, the innate immune cells, such as macrophages, may contribute, in some cases, to the disease progression Macrophages have shown a significant production of IL-6 suggesting they may contribute to the excessive inflammation in COVID-19 disease Macrophage Activation Syndrome may further explain the high serum levels of CRP, which are normally lacking in viral infections In adaptive immune responses, it has been revealed that cytotoxic CD8+ T cells exhibit functional exhaustion patterns, such as the expression of NKG2A, PD-1, and TIM-3 Since SARS-CoV-2 restrains antigen presentation by downregulating MHC class I and II molecules and, therefore, inhibits the T cell-mediated immune responses, humoral immune responses also play a substantial role Specific IgA response appears to be stronger and more persistent than IgM response Moreover, IgM and IgG antibodies show similar dynamics in COVID-19 disease

Title: COVID-19: Immunology and treatment options Content: Abstract The novel coronavirus SARS-CoV2 causes COVID-19, a pandemic threatening millions. As protective immunity does not exist in humans and the virus is capable of escaping innate immune responses, it can proliferate, unhindered, in primarily infected tissues. Subsequent cell death results in the release of virus particles and intracellular components to the extracellular space, which result in immune cell recruitment, the generation of immune complexes and associated damage. Infection of monocytes/macrophages and/or recruitment of uninfected immune cells can result in massive inflammatory responses later in the disease. Uncontrolled production of pro-inflammatory mediators contributes to ARDS and cytokine storm syndrome. Antiviral agents and immune modulating treatments are currently being trialled. Understanding immune evasion strategies of SARS-CoV2 and the resulting delayed massive immune response will result in the identification of biomarkers that predict outcomes as well as phenotype and disease stage specific treatments that will likely include both antiviral and immune modulating agents.

Title: Inflammatory markers in Covid-19 Patients: a systematic review and meta-analysis. Content: Introduction Diagnosis of COVID-19 is based on clinical manifestation, history of exposure, positive findings on chest CT and laboratory tests. It has been shown that inflammation plays a role in pathogenesis of COVID-19. Method We used the necessary transformations to convert the median and IQR to mean and SD Random-effect model using Der Simonian, and Laird methods was used if heterogeneity between studies was significant, the homogeneity among studies was assessed with I2 Statistic, values above 50%, and for the chi-square test, P-values <0.1 was supposed statistically significant Results Twelve studies were included in the analysis that all of which were conducted in China in the year 2020. The result of combining 12 articles with 772 participants showed that the pooled estimate of the mean of lymphocyte with 95% CI was (Mean: 1.01; 95% CI (0.76-1.26); p-value<0.001). About WBC the pooled result of 9 studies with 402 participants was (Mean: 5.11; 95% CI (3.90-6.32); p-value<0.001) Also the pooled mean estimate of 9 studies with 513 patients for the ratio of Neutrophil/lymphocyte was (Mean: 3.62; 95% CI (1.48-5.77); p-value=0.001). The pooled mean from the combination of 7 studies with 521 patients on CRP was (Mean: 28.75; 95% CI (8.04-49.46). Conclusion Inflammatory Markers increase in patients with Covid-19, which can be a good indicator to find patients.

Title: COVID-19 cytokine storm: The anger of inflammation Content: Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.

Title: p38 MAPK inhibition: A promising therapeutic approach for COVID-19 Content: COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1–7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1–7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.

Title: COVID-19 and the immune system. Content: A close interaction between the virus SARS-CoV-2 and the immune system of an individual results in a diverse clinical manifestation of the COVID-19 disease. While adaptive immune responses are essential for SARS-CoV-2 virus clearance, the innate immune cells, such as macrophages, may contribute, in some cases, to the disease progression. Macrophages have shown a significant production of IL-6 suggesting they may contribute to the excessive inflammation in COVID-19 disease. Macrophage Activation Syndrome may further explain the high serum levels of CRP, which are normally lacking in viral infections. In adaptive immune responses, it has been revealed that cytotoxic CD8+ T cells exhibit functional exhaustion patterns, such as the expression of NKG2A, PD-1, and TIM-3. Since SARS-CoV-2 restrains antigen presentation by downregulating MHC class I and II molecules and, therefore, inhibits the T cell-mediated immune responses, humoral immune responses also play a substantial role. Specific IgA response appears to be stronger and more persistent than IgM response. Moreover, IgM and IgG antibodies show similar dynamics in COVID-19 disease.

Title: Severe COVID-19: A Review of Recent Progress With a Look Toward the Future Content: The novel coronavirus disease 2019 (COVID-19) is an acute infectious disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, the World Health Organization has confirmed that COVID-19 is a global infectious disease pandemic. This is the third acute infectious disease caused by coronavirus infection in this century, after sudden acute respirator syndrome and Middle East respiratory syndrome. The damage mechanism of SARS-CoV-2 is still unclear. It is possible that protein S binds to angiotensin-converting enzyme 2 receptors and invades alveolar epithelial cells, causing direct toxic effects and an excessive immune response. This stimulates a systemic inflammatory response, thus forming a cytokine storm, which leads to lung tissue injury. In severe cases, the disease can lead to acute respiratory distress syndrome, septic shock, metabolic acidosis, coagulation dysfunction, and multiple organ dysfunction syndromes. Patients with severe COVID-19 have a relatively high mortality rate. Currently, there are no specific antiviral drugs for the treatment of COVID-19. Most patients need to be admitted to the intensive care unit for intensive monitoring and supportive organ function treatments. This article reviews the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment methods of severe COVID-19 and puts forward some tentative ideas, aiming to provide some guidance for the diagnosis and treatment of severe COVID-19.

Title: The COVID-19 Cytokine Storm; What We Know So Far Content: COVID-19 is a rapidly spreading global threat that has been declared as a pandemic by the WHO. COVID-19 is transmitted via droplets or direct contact and infects the respiratory tract resulting in pneumonia in most of the cases and acute respiratory distress syndrome (ARDS) in about 15 % of the cases. Mortality in COVID-19 patients has been linked to the presence of the so-called "cytokine storm" induced by the virus. Excessive production of proinflammatory cytokines leads to ARDS aggravation and widespread tissue damage resulting in multi-organ failure and death. Targeting cytokines during the management of COVID-19 patients could improve survival rates and reduce mortality.

Title: p38 MAPK inhibition: A promising therapeutic approach for COVID-19 Content: COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1-7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1-7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.

Title: Potential Mechanisms of Cardiac Injury and Common Pathways of Inflammation in Patients With COVID-19 Content: Due to the lack of prospective, randomized, controlled clinical studies on inflammation and cardiovascular involvement, the exact mechanism of cardiac injury among patients with Coronavirus Disease 2019 (COVID-19) still remains uncertain. It was demonstrated that there is a high and significantly positive linear correlation between troponin T and plasma high-sensitivity C-reactive protein levels, biomarkers of cardiac injury and systemic inflammation, respectively. Cardiac injury and inflammation is a relatively common association among patients hospitalized with COVID-19, and it is related to higher risk of in-hospital mortality. In our literature search, we identified several potential mechanisms of myocardial tissue damage, namely, coronavirus-associated acute myocarditis, angiotensin-converting enzyme 2 receptor binding affinity to the virus Spike protein, increased cytokine secretion, and hypoxia-induced cardiac myocyte apoptosis. Elucidation of the disease pathogenesis and prospective histopathological studies are crucial for future proper treatment in case of renewed outbreaks. Of interest is that with hundred of thousands of bodies available for autopsy studies, no prospective investigation has been reported so far. Strong efforts and continued research of the cardiovascular complications and identification of risk factors for poor prognosis in COVID-19 are steadily needed. The high morbidity and mortality of COVID-19, its monumental economic burden and social impact, the despair of a new pandemic outbreak, and the thread of potential utilization of novel severe acute respiratory syndrome coronavirus 2 as biologic weapons make it a preponderant necessity to better comprehend the therapeutic management of this lethal disease. Emerging as an acute infectious disease, COVID-19 may become a chronic epidemic because of genetic recombination. Therefore, we should be ready for the reemergence of COVID-19 or other coronaviruses.

Title: COVID-19: Review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross-talking Content: SARS-CoV-2 is the agent responsible for COVID-19. The infection can be dived into three phases: mild infection, the pulmonary phase and the inflammatory phase. Treatment options for the pulmonary phase include: Hydroxychloroquine, Remdesivir, Lopinavir/Ritonavir. The inflammatory phase includes therapeutic options like Tocilizumab, Anakinra, Baricitinib, Eculizumab, Emapalumab and Heparin. Human clinical trials are starting to show some results, in some cases like that of Remdesivir and corticosteroids these are controversial. Coagulopathy is a common complication in severe cases, inflammation and coagulation are intertwined and cross-talking between these two responses is known to happen. A possible amplification of this cross-talking is suggested to be implicated in the severe cases that show both a cytokine storm and coagulopathy.

Title: Immune Status of COVID-19 Patients with Reference to SARS and MERS Content: During this global pandemic of COVID-19 infection, it became well known that morbidity and mortality is especially high at the extreme of life especially in certain racial or ethnic groups like Americans and Africans This is presumed due to low immunity associated with other comorbid conditions like diabetes, hypertension, cardiovascular disease, obesity and metabolic syndrome But the information available on the immune status of COVID-19 patients is limited Attempts must be made to enhance our understanding of the immune status of COVID-19 patients by revisiting our knowledge on the immune mechanisms of already known coronaviruses such as SARS-CoV and MERS-CoV Early elevation of the serum levels of pro-inflammatory cytokines observed in SARS and MERS infection suggests a possible same type of cytokine storm-mediated lung damage in COVID-19 patients too Dysregulation of interferon-1 response and downstream cascade in initial innate immune response at virus entry point has been related to lethal pneumonia in COVID-19 patients Adaptive response of increased CD8+ levels in COVID-19 patients seems to be useful in mild cases where it causes deteriorating effects in progressed severe disease patients resulting in destruction of type 2 pneumocytes hence inability to regenerate the alveolar epithelium A phenomenon called cytokine storm activates violent immunological reactions in the lung tissue resulting in ARDS followed by multiple organ system damages in COVID-19 patients Several immune evading mechanisms are thought to be employed by severe respiratory syndrome virus-2 (SARS-CoV-2) that might have resulted in its extremely increased contagiousness probably related with its frequent RNA mutations Failure to develop adequate virus limiting immune reactions by some cured patients warrant monitoring of all recovered patients This rapid mini review is aimed to enhance our knowledge of the immune status of COVID-19 infected patients with reference to SARS-CoV and MERS-CoV

Title: Inflammatory and Coagulative Considerations for the Management of Orthopaedic Trauma Patients with COVID-19: A Review of the Current Evidence and Our Surgical Experience Content: Mounting evidence suggests that the pathogenesis of coronavirus disease 2019 (COVID-19) involves a hyperinflammatory response predisposing patients to thromboembolic disease and acute respiratory distress. In the setting of severe blunt trauma, damaged tissues induce a local and systemic inflammatory response through similar pathways to COVID-19. As such, patients with COVID-19 sustaining orthopaedic trauma injuries may have an amplified response to the traumatic insult due to their baseline hyperinflammatory and hypercoagulable state. These patients may have compromised physiological reserve to withstand the insult of surgical intervention before reaching clinical instability. Herein, we review the current evidence regarding pathogenesis of COVID-19 and its implications on the management of orthopaedic trauma patients by discussing a case and the most recent literature.

Title: COVID-19: Immunology and treatment options Content: The novel coronavirus SARS-CoV2 causes COVID-19, a pandemic threatening millions. As protective immunity does not exist in humans and the virus is capable of escaping innate immune responses, it can proliferate, unhindered, in primarily infected tissues. Subsequent cell death results in the release of virus particles and intracellular components to the extracellular space, which result in immune cell recruitment, the generation of immune complexes and associated damage. Infection of monocytes/macrophages and/or recruitment of uninfected immune cells can result in massive inflammatory responses later in the disease. Uncontrolled production of pro-inflammatory mediators contributes to ARDS and cytokine storm syndrome. Antiviral agents and immune modulating treatments are currently being trialled. Understanding immune evasion strategies of SARS-CoV2 and the resulting delayed massive immune response will result in the identification of biomarkers that predict outcomes as well as phenotype and disease stage specific treatments that will likely include both antiviral and immune modulating agents.

Title: Possible Cause of Inflammatory Storm and Septic Shock in Patients Diagnosed with (COVID-19) Content: The novel coronavirus (SARS-CoV-2) infection which has been known as Coronavirus diseases 2019 COVID-19 has become an endemic emergent situation by the World Health Organization. So far, no successful specific treatment has been found for this disease. As has been reported, most of non-survivor patients with COVID-19 (70%) had septic shock which was significantly higher than survived ones. Although the exact pathophysiology of septic shock in these patients is still unclear, it seems to be possible that part of it would be due to the administration of empiric antibiotics with inflammatory properties especially in the absence of bacterial infection. Herein, we have reviewed possible molecular pathways of septic shock in the patients who have received antibiotics with inflammatory properties which mainly is release of interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF- α) through different routes. Altogether, we highly recommend clinicians to look after those antibiotics with anti-inflammatory activity for both empiric antibiotic therapy and reducing the inflammation to prevent septic shock in patients with diagnosed COVID-19.

Title: COVID-19: review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross-talking Content: SARS-CoV-2 is the agent responsible for COVID-19. The infection can be dived into three phases: mild infection, the pulmonary phase and the inflammatory phase. Treatment options for the pulmonary phase include: Hydroxychloroquine, Remdesivir, Lopinavir/Ritonavir. The inflammatory phase includes therapeutic options like Tocilizumab, Anakinra, Baricitinib, Eculizumab, Emapalumab and Heparin. Human clinical trials are starting to show some results, in some cases like that of Remdesivir these are controversial. Coagulopathy is a common complication in severe cases, inflammation and coagulation are intertwined and cross-talking between these two responses is known to happen. A possible amplification of this cross-talking is suggested to be implicated in the severe cases that show both a cytokine storm and coagulopathy.

Title: SGLT2 inhibition and COVID-19: The road not taken Content: The COVID-19 pandemic, caused by SARS-CoV-2, is an immense challenge for global healthcare. Diabetes mellitus, hypertension and obesity have been shown to portend poor prognosis in COVID-19 despite no greater susceptibility to the infection (1). Chronic hypertension is commonly associated with vasculopathy which can predispose to severe infection. In patients with diabetes, severity is attributable to impaired innate, adaptive immunity, upregulation of ACE2 (entry receptor for SARS-CoV2) by acute hyperglycemia and diabetic vasculopathy. The background of chronic low grade inflammation characterised by increased levels of IL-6 and CRP in diabetes and obesity can also lead to an enhanced 'cytokine storm' in COVID-19 (2). ACE2 expression on endothelial cells has been reported to cause viral mediated endothelitis and precipitate vascular dysfunction manifesting as acute respiratory distress syndrome as well as myocarditis, heart failure, arrhythmias, myocardial infarction and renal failure (3). In patients with pre-existing comorbidities like hypertension, diabetes, obesity and chronic kidney disease, this new-onset organ dysfunction can have deleterious additive effects.

Title: SGLT2 inhibition and COVID-19: The road not taken. Content: The COVID-19 pandemic, caused by SARS-CoV-2, is an immense challenge for global healthcare. Diabetes mellitus, hypertension and obesity have been shown to portend poor prognosis in COVID-19 despite no greater susceptibility to the infection (1). Chronic hypertension is commonly associated with vasculopathy which can predispose to severe infection. In patients with diabetes, severity is attributable to impaired innate, adaptive immunity, upregulation of ACE2 (entry receptor for SARS-CoV2) by acute hyperglycemia and diabetic vasculopathy. The background of chronic low grade inflammation characterised by increased levels of IL-6 and CRP in diabetes and obesity can also lead to an enhanced 'cytokine storm' in COVID-19 (2). ACE2 expression on endothelial cells has been reported to cause viral mediated endothelitis and precipitate vascular dysfunction manifesting as acute respiratory distress syndrome as well as myocarditis, heart failure, arrhythmias, myocardial infarction and renal failure (3). In patients with pre-existing comorbidities like hypertension, diabetes, obesity and chronic kidney disease, this new-onset organ dysfunction can have deleterious additive effects.

Title: Myocardial injury and COVID-19: Possible mechanisms Content: Coronavirus Disease 2019 (COVID-19) has quickly progressed to a global health emergency. Respiratory illness is the major cause of morbidity and mortality in these patients with the disease spectrum ranging from asymptomatic subclinical infection, to severe pneumonia progressing to acute respiratory distress syndrome. There is growing evidence describing pathophysiological resemblance of SARS-CoV-2 infection with other coronavirus infections such as Severe Acute Respiratory Syndrome coronavirus and Middle East Respiratory Syndrome coronavirus (MERS-CoV). Angiotensin Converting Enzyme-2 receptors play a pivotal role in the pathogenesis of the virus. Disruption of this receptor leads to cardiomyopathy, cardiac dysfunction, and heart failure. Patients with cardiovascular disease are more likely to be infected with SARS-CoV-2 and they are more likely to develop severe symptoms. Hypertension, arrhythmia, cardiomyopathy and coronary heart disease are amongst major cardiovascular disease comorbidities seen in severe cases of COVID-19. There is growing literature exploring cardiac involvement in SARS-CoV-2. Myocardial injury is one of the important pathogenic features of COVID-19. As a surrogate for myocardial injury, multiple studies have shown increased cardiac biomarkers mainly cardiac troponins I and T in the infected patients especially those with severe disease. Myocarditis is depicted as another cause of morbidity amongst COVID-19 patients. The exact mechanisms of how SARS-CoV-2 can cause myocardial injury are not clearly understood. The proposed mechanisms of myocardial injury are direct damage to the cardiomyocytes, systemic inflammation, myocardial interstitial fibrosis, interferon mediated immune response, exaggerated cytokine response by Type 1 and 2 helper T cells, in addition to coronary plaque destabilization, and hypoxia.

Title: Immune environment modulation in pneumonia patients caused by coronavirus: SARS-CoV, MERS-CoV and SARS-CoV-2 Content: Currently, we are on a global pandemic of Coronavirus disease-2019 (COVID-19) which causes fever, dry cough, fatigue and acute respiratory distress syndrome (ARDS) that may ultimately lead to the death of the infected. Current researches on COVID-19 continue to highlight the necessity for further understanding the virus-host synergies. In this study, we have highlighted the key cytokines induced by coronavirus infections. We have demonstrated that genes coding interleukins (Il-1α, Il-1ß, Il-6, Il-10), chemokine (Ccl2, Ccl3, Ccl5, Ccl10), and interferon (Ifn-α2, Ifn-ß1, Ifn2) upsurge significantly which in line with the elevated infiltration of T cells, NK cells and monocytes in SARS-Cov treated group at 24 hours. Also, interleukins (IL-6, IL-23α, IL-10, IL-7, IL-1α, IL-1ß) and interferon (IFN-α2, IFN2, IFN-Î³) have increased dramatically in MERS-Cov at 24 hours. A similar cytokine profile showed the cytokine storm served a critical role in the infection process. Subsequent investigation of 463 patients with COVID-19 disease revealed the decreased amount of total lymphocytes, CD3+, CD4+, and CD8+ T lymphocytes in the severe type patients which indicated COVID-19 can impose hard blows on human lymphocyte resulting in lethal pneumonia. Thus, taking control of changes in immune factors could be critical in the treatment of COVID-19.

Title: Estudios de imagen cardiaca en la pandemia COVID-19 Content: COVID-19 is an acute respiratory syndrome caused by coronavirus-2 (SARS COV2) The different cardiac imaging methods have issued specific recommendations for the different imaging methods in this pandemic, so it is essential to emphasize the recommendations for carrying out these studies

Title: Unraveling the mystery of Covid-19 Cytokine storm: From skin to organ systems Content: COVID-19 is a global pandemic that emerged from Wuhan, China. Besides pneumonia and acute respiratory distress syndrome, the disease leads to multisystem involvement in the form of myocarditis, arrhythmias, cardiac arrest, gastrointestinal symptoms, hypoxemic brain injury, acute liver and renal function impairment. There are also reports of cutaneous lesions in form of urticarial and maculopapular rashes, chilblain like fingers and toes (covid feet), livedoid vasculopathy and chicken-pox like or varicelliform vesicles. Clinically, many of these skin lesions are likely secondary to occlusion of small to medium blood vessels due to microthrombi formation or due to viral laden antigen-antibody immune complexes; and same explanation may hold true for possible hypoxemic injury simultaneously occurring in other vital organs like lungs, heart, brain and kidneys. The histopathology, immunoflorescence and RT-PCR analysis of skin biopsies can provide useful insights for ascertaining the pathogenesis of this complex viral syndrome. Apparently, it is interplay of disarmed cellular immunity and over-activated humoral immunity that culminates in end-organ changes. The morbidity and mortality can be significantly reduced by upgrading the cellular immunity and downgrading the humoral response; along with prevention of hypoxemic and reperfusion injuries by using antivirals, immunomodulators, antioxidants, anti-platelets and anticoagulants in judicious and phased manner. This article is protected by copyright. All rights reserved.

Title: Inflammatory and Coagulative Considerations for the Management of Orthopaedic Trauma Patients With COVID-19: A Review of the Current Evidence and Our Surgical Experience Content: Mounting evidence suggests that the pathogenesis of coronavirus disease 2019 (COVID-19) involves a hyperinflammatory response predisposing patients to thromboembolic disease and acute respiratory distress. In the setting of severe blunt trauma, damaged tissues induce a local and systemic inflammatory response through similar pathways to COVID-19. As such, patients with COVID-19 sustaining orthopaedic trauma injuries may have an amplified response to the traumatic insult because of their baseline hyperinflammatory and hypercoagulable states. These patients may have compromised physiological reserve to withstand the insult of surgical intervention before reaching clinical instability. In this article, we review the current evidence regarding pathogenesis of COVID-19 and its implications on the management of orthopaedic trauma patients by discussing a case and the most recent literature.

Title: Estudios de imagen cardiaca en la pandemia COVID-19./ Cardiac imaging studies in the COVID-19 pandemic Content: COVID-19 is an acute respiratory syndrome caused by coronavirus-2 (SARS COV2). The different cardiac imaging methods have issued specific recommendations for the different imaging methods in this pandemic, so it is essential to emphasize the recommendations for carrying out these studies.

Title: Cardiac imaging studies in the COVID-19 pandemic. Content: COVID-19 is an acute respiratory syndrome caused by coronavirus-2 (SARS COV2). The different cardiac imaging methods have issued specific recommendations for the different imaging methods in this pandemic, so it is essential to emphasize the recommendations for carrying out these studies.

Title: Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: A novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis Content: Early clinical evidence suggests that severe cases of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are frequently characterized by hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy, and intravascular coagulopathy. In this paper, we present an immunothrombosis model of COVID-19. We discuss the underlying pathogenesis and the interaction between multiple systems, resulting in propagation of immunothrombosis, which through investigation in the coming weeks, may lead to both an improved understanding of COVID-19 pathophysiology and identification of innovative and efficient therapeutic targets to reverse the otherwise unfavorable clinical outcome of many of these patients.

Title: Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic Content: Coronavirus disease-2019 (COVID-19) infection and its severity can be explained by the concentration of glycosylated severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral particles in the lung epithelium, the concentration of glycosylated angiotensin-converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS-CoV-2 spike protein at approximately day 8 to 10 after symptom onset, which may be related to both. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID-19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS-CoV-2 spike protein form at day 7 to 10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular, those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS.

Title: The COVID-19 Cytokine Storm; What We Know So Far Content: COVID-19 is a rapidly spreading global threat that has been declared as a pandemic by the WHO. COVID-19 is transmitted via droplets or direct contact and infects the respiratory tract resulting in pneumonia in most of the cases and acute respiratory distress syndrome (ARDS) in about 15 % of the cases. Mortality in COVID-19 patients has been linked to the presence of the so-called “cytokine storm” induced by the virus. Excessive production of proinflammatory cytokines leads to ARDS aggravation and widespread tissue damage resulting in multi-organ failure and death. Targeting cytokines during the management of COVID-19 patients could improve survival rates and reduce mortality.

Title: Immune environment modulation in pneumonia patients caused by coronavirus: SARS-CoV, MERS-CoV and SARS-CoV-2 Content: Currently, we are on a global pandemic of Coronavirus disease-2019 (COVID-19) which causes fever, dry cough, fatigue and acute respiratory distress syndrome (ARDS) that may ultimately lead to the death of the infected. Current researches on COVID-19 continue to highlight the necessity for further understanding the virus-host synergies. In this study, we have highlighted the key cytokines induced by coronavirus infections. We have demonstrated that genes coding interleukins (Il-1α, Il-1β, Il-6, Il-10), chemokine (Ccl2, Ccl3, Ccl5, Ccl10), and interferon (Ifn-α2, Ifn-β1, Ifn2) upsurge significantly which in line with the elevated infiltration of T cells, NK cells and monocytes in SARS-Cov treated group at 24 hours. Also, interleukins (IL-6, IL-23α, IL-10, IL-7, IL-1α, IL-1β) and interferon (IFN-α2, IFN2, IFN-γ) have increased dramatically in MERS-Cov at 24 hours. A similar cytokine profile showed the cytokine storm served a critical role in the infection process. Subsequent investigation of 463 patients with COVID-19 disease revealed the decreased amount of total lymphocytes, CD3+, CD4+, and CD8+ T lymphocytes in the severe type patients which indicated COVID-19 can impose hard blows on human lymphocyte resulting in lethal pneumonia. Thus, taking control of changes in immune factors could be critical in the treatment of COVID-19.

Title: Coronavirus Disease 2019 (COVID-19): Cytokine Storms, Hyper-Inflammatory Phenotypes, and Acute Respiratory Distress Syndrome Content: Abstract Coronavirus Disease 2019 (COVID-19) was first identified in China at the end of 2019. Acute respiratory distress syndrome (ARDS) represents the most common and serious complication of COVID-19. Cytokine storms are a pathophysiological feature of COVID-19 and play an important role in distinguishing hyper-inflammatory subphenotypes of ARDS. Accordingly, in this review, we focus on hyper-inflammatory host responses in ARDS that play a critical role in the differentiated development of COVID-19. Furthermore, we discuss inflammation-related indicators that have the potential to identify hyper-inflammatory subphenotypes of COVID-19, especially for those with a high risk of ARDS. Finally, we explore the possibility of improving the quality of monitoring and treatment of COVID-19 patients and in reducing the incidence of critical illness and mortality via better distinguishing hyper- and hypo-inflammatory subphenotypes of COVID-19.

Title: Myocardial injury and COVID-19: Possible mechanisms Content: Abstract Coronavirus Disease 2019 (COVID-19) has quickly progressed to a global health emergency. Respiratory illness is the major cause of morbidity and mortality in these patients with the disease spectrum ranging from asymptomatic subclinical infection, to severe pneumonia progressing to acute respiratory distress syndrome. There is growing evidence describing pathophysiological resemblance of SARS-CoV-2 infection with other coronavirus infections such as Severe Acute Respiratory Syndrome coronavirus and Middle East Respiratory Syndrome coronavirus (MERS-CoV). Angiotensin Converting Enzyme-2 receptors play a pivotal role in the pathogenesis of the virus. Disruption of this receptor leads to cardiomyopathy, cardiac dysfunction, and heart failure. Patients with cardiovascular disease are more likely to be infected with SARS-CoV-2 and they are more likely to develop severe symptoms. Hypertension, arrhythmia, cardiomyopathy and coronary heart disease are amongst major cardiovascular disease comorbidities seen in severe cases of COVID-19. There is growing literature exploring cardiac involvement in SARS-CoV-2. Myocardial injury is one of the important pathogenic features of COVID-19. As a surrogate for myocardial injury, multiple studies have shown increased cardiac biomarkers mainly cardiac troponins I and T in the infected patients especially those with severe disease. Myocarditis is depicted as another cause of morbidity amongst COVID-19 patients. The exact mechanisms of how SARS-CoV-2 can cause myocardial injury are not clearly understood. The proposed mechanisms of myocardial injury are direct damage to the cardiomyocytes, systemic inflammation, myocardial interstitial fibrosis, interferon mediated immune response, exaggerated cytokine response by Type 1 and 2 helper T cells, in addition to coronary plaque destabilization, and hypoxia.

Title: Immune Response, Inflammation, and the Clinical Spectrum of COVID-19 Content: The current COVID-19 pandemic began in December 2019 in Wuhan (China) and rapidly extended to become a global sanitary and economic emergency. Its etiological agent is the coronavirus SARS-CoV-2. COVID-19 presents a wide spectrum of clinical manifestations, which ranges from an asymptomatic infection to a severe pneumonia accompanied by multisystemic failure that can lead to a patient's death. The immune response to SARS-CoV-2 is known to involve all the components of the immune system that together appear responsible for viral elimination and recovery from the infection. Nonetheless, such immune responses are implicated in the disease's progression to a more severe and lethal process. This review describes the general aspects of both COVID-19 and its etiological agent SARS-CoV-2, stressing the similarities with other severe coronavirus infections, such as SARS and MERS, but more importantly, pointing toward the evidence supporting the hypothesis that the clinical spectrum of COVID-19 is a consequence of the corresponding variable spectrum of the immune responses to the virus. The critical point where progression of the disease ensues appears to center on loss of the immune regulation between protective and altered responses due to exacerbation of the inflammatory components. Finally, it appears possible to delineate certain major challenges deserving of exhaustive investigation to further understand COVID-19 immunopathogenesis, thus helping to design more effective diagnostic, therapeutic, and prophylactic strategies.

Title: Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID-19 Content: Background: SARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the pathogenesis and outcome of COVID-19. We aimed to investigate which specific responses from either cellular or humoral immunity associate to severity and progression of COVID-19. Methods: A cohort of 276 patients classified in mild, moderate and severe, was studied. Peripheral blood lymphocyte subpopulations were quantified by flow cytometry, and immunoglobulins and complement proteins by nephelometry. Results: At admission, dramatic lymphopenia of T, B and NK cells associated to severity. However, only the proportion of B cells increased, while T and NK cells appeared unaffected. Accordingly, the number of plasma cells and circulating follicular helper T cells (cTfh) increased, but levels of IgM, IgA and IgG were unaffected. When degrees of severity were considered, IgG was lower in severe patients, suggesting an IgG consumption by complement activation or antibody-dependent cellular cytotoxicity (ADCC). Activated CD56-CD16+ NK-cells, which mediate ADCC, were increased. Regarding complement, C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, compared to healthy donors. Moreover, IgG and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Conclusion: Our study provides important clues to understand the immune response observed in COVID-19 patients, which is probably related to viral clearance, but also underlies its pathogenesis and severity. This study associates for the first time COVID-19 severity with an imbalanced humoral immune response characterized by excessive consumption of IgG and C4, identifying new targets for therapeutic intervention.

Title: Biochemical indicators of coronavirus disease 2019 exacerbation and the clinical implications Content: Coronavirus Disease 2019 (COVID-19) has sparked a global pandemic, affecting more than 4 million people worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause acute lung injury (ALI) and even acute respiratory distress syndrome (ARDS); with a fatality of 7.0 %. Accumulating evidence suggested that the progression of COVID-19 is associated with lymphopenia and excessive inflammation, and a subset of severe cases might exhibit cytokine storm triggered by secondary hemophagocytic lymphohistiocytosis (sHLH). Furthermore, secondary bacterial infection may contribute to the exacerbation of COVID-19. We recommend using both IL-10 and IL-6 as the indicators of cytokine storm, and monitoring the elevation of procalcitonin (PCT) as an alert for initiating antibacterial agents. Understanding the dynamic progression of SARS-CoV-2 infection is crucial to determine an effective treatment strategy to reduce the rising mortality of this global pandemic.

Title: The renin-angiotensin-aldosterone system: Role in pathogenesis and potential therapeutic target in COVID-19 Content: Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 novel coronavirus, has spread worldwide causing high fatality rates. Neither a vaccine nor specific therapeutic approaches are available, hindering the fight against this disease and making better understanding of its pathogenesis essential. Despite similarities between SARS-CoV-2 and SARS-CoV, the former has unique characteristics which represent a great challenge to physicians. The mechanism of COVID-19 infection and pathogenesis is still poorly understood. In the present review, we highlight possible pathways involved in the pathogenesis of COVID-19 and potential therapeutic targets, focusing on the role of the renin-angiotensin-aldosterone system.

Title: The renin-angiotensin-aldosterone system: Role in pathogenesis and potential therapeutic target in COVID-19. Content: Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 novel coronavirus, has spread worldwide causing high fatality rates. Neither a vaccine nor specific therapeutic approaches are available, hindering the fight against this disease and making better understanding of its pathogenesis essential. Despite similarities between SARS-CoV-2 and SARS-CoV, the former has unique characteristics which represent a great challenge to physicians. The mechanism of COVID-19 infection and pathogenesis is still poorly understood. In the present review, we highlight possible pathways involved in the pathogenesis of COVID-19 and potential therapeutic targets, focusing on the role of the renin-angiotensin-aldosterone system.

Title: Electrical Storm in COVID-19 Content: Abstract COVID-19 is a global pandemic caused by SARS-CoV-2. Infection is associated with significant morbidity and mortality. Individuals with pre-existing cardiovascular disease or evidence of myocardial injury are at risk for severe disease and death. Little is understood about the mechanisms of myocardial injury or life-threatening cardiovascular sequelae.

Title: Characteristics of inflammatory factors and lymphocyte subsets in patients with severe COVID-19 Content: To investigate the inflammatory factors and lymphocyte subsets which play an important role in the course of severe coronavirus disease 2019 (COVID-19). A total of 27 patients with severe COVID-19 who were admitted to Tongji Hospital in Wuhan from 1 to 21 February 2020 were recruited to the study. The characteristics of interleukin-1ß (IL-1ß), IL-2 receptor (IL-2R), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF)-α, C-reactive protein (CRP), serum ferritin and procalcitonin (PCT), and lymphocyte subsets of these patients were retrospectively compared before and after treatment. Before treatment, there was no significant difference in most inflammatory factors (IL-1ß, IL-2R, IL-6, IL-8, IL-10, CRP, and serum ferritin) between male and female patients. Levels of IL-2R, IL-6, TNF-α, and CRP decreased significantly after treatment, followed by IL-8, IL-10, and PCT. Serum ferritin was increased in all patients before treatment but did not decrease significantly after treatment. IL-1ß was normal in most patients before treatment. Lymphopenia was common among these patients with severe COVID-19. Analysis of lymphocyte subsets showed that CD4+ and particularly CD8+ T lymphocytes increased significantly after treatment. However, B lymphocytes and natural killer cells showed no significant changes after treatment. A pro-inflammatory response and decreased level of T lymphocytes were associated with severe COVID-19.

Title: Tackle the free radicals damage in COVID-19. Content: COVID-19 is a severe pandemic which has caused a devastating amount of loss in lives around the world, and yet we still don't know how to appropriately treat this disease. We know very little about the pathogenesis of SARS-CoV-2, the virus which induces the COVID-19. However, COVID-19 does share many similar symptoms with SARS and influenza. Previous scientific discoveries learned from lab animal models and clinical practices shed light on possible pathogenic mechanisms in COVID-19. In the past decades, accumulated scientific findings confirmed the pathogenic role of free radicals damage in respiratory virus infection. Astonishingly very few medical professionals mention the crucial role of free radical damage in COVID-19. This hypothesis aims to summarize the crucial pathogenic role of free radical damage in respiratory virus induced pneumonia and suggest an antioxidative therapeutic strategy for COVID-19.

Title: Targeting Cytokine Storm to Manage Patients with COVID-19: A Mini-Review Content: Abstract Corona Virus Disease 2019 (COVID-19) pandemic is rapidly spreading all over the world. Excessive immune responses trigger life-threatening cytokine release syndrome (CRS) which can result in overproduction of pro-inflammatory cytokines including tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1β with different pro-inflammatory roles. Anecdotal evidence suggests that the modulation of systemic immune responses may have a potential role in the treatment of patients with COVID-19. Given the importance of the issue and the lack of therapeutic treatment or vaccine; anti-cytokine therapy such as IL-6, TNFα and IL-1 antagonists have been suggested for the alleviation of hyper-inflammation status in these patients. In this mini-review, we addressed the inflammatory pathways of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its relationship with the host cytokine storm. Furthermore, the proposed therapeutic options to reverse hyper-inflammation in infected patients were mentioned.

Title: Inflammation: A bridge between Diabetes and COVID-19, and possible management with sitagliptin Content: Patients with SARS-CoV-2 infections experience lymphopenia and inflammatory cytokine storms in the severe stage of the disease, leading to multi-organ damage. The exact pattern of immune system changes and their condition during the disease process is unclear. The available knowledge has indicated that the NF-kappa-B pathway, which is induced by several mediators, has a significant role in cytokine storm through the various mechanisms. Therefore, identifying the state of the immune cells and the dominant mechanisms for the production of cytokines incorporated in the cytokine storm can be a critical step in the therapeutic approach. On the other hand, some studies identified a higher risk for diabetic patients. Diabetes mellitus exhibits a close association with inflammation and increases the chance of developing COVID-19. Patients with diabetes mellitus have shown to have more virus entry, impaired immunity response, less viral elimination, and dysregulated inflammatory cytokines. The parallel analysis of COVID-19 and diabetes mellitus pathogenesis has proposed that the control of the inflammation through the interfering with the critical points of major signaling pathways may provide the new therapeutic approaches. In recent years, the role of Dipeptidyl Peptidase 4 (DPP4) in chronic inflammation has been proved. Numerous immune cells express the DPP4 protein. DPP4 regulates antibody production, cytokine secretion, and immunoglobulin class switching. DPP4 inhibitors like sitagliptin reduce inflammation intensity in different states. Following the accumulating data, we hypothesize that sitagliptin might reduce COVID-19 severity. Sitagliptin, an available DPP4 inhibitor drug, showed multidimensional anti-inflammatory effects among diabetic patients. It reduces the inflammation mostly by affecting on NF-kappa-B signaling pathway. Under the fact that inflammatory mediators are active in individuals with COVID-19, blocking the predominant pathway could be helpful.

Title: COVID-19 as an Acute Inflammatory Disease Content: The 2019 coronavirus disease (COVID-19) pandemic caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has created an unprecedented global crisis for the infrastructure sectors, including economic, political, healthcare, education, and research systems. Although over 90% of infected individuals are asymptomatic or manifest noncritical symptoms and will recover from the infection, those individuals presenting with critical symptoms are in urgent need of effective treatment options. Emerging data related to mechanism of severity and potential therapies for patients presenting with severe symptoms are scattered and therefore require a comprehensive analysis to focus research on developing effective therapeutics. A critical literature review suggests that the severity of SARS-CoV-2 infection is associated with dysregulation of inflammatory immune responses, which in turn inhibits the development of protective immunity to the infection. Therefore, the use of therapeutics that modulate inflammation without compromising the adaptive immune response could be the most effective therapeutic strategy.

Title: COVID-19 as an Acute Inflammatory Disease. Content: The 2019 coronavirus disease (COVID-19) pandemic caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has created an unprecedented global crisis for the infrastructure sectors, including economic, political, healthcare, education, and research systems. Although over 90% of infected individuals are asymptomatic or manifest noncritical symptoms and will recover from the infection, those individuals presenting with critical symptoms are in urgent need of effective treatment options. Emerging data related to mechanism of severity and potential therapies for patients presenting with severe symptoms are scattered and therefore require a comprehensive analysis to focus research on developing effective therapeutics. A critical literature review suggests that the severity of SARS-CoV-2 infection is associated with dysregulation of inflammatory immune responses, which in turn inhibits the development of protective immunity to the infection. Therefore, the use of therapeutics that modulate inflammation without compromising the adaptive immune response could be the most effective therapeutic strategy.

Title: Rheumatologists’ perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets Content: The ongoing pandemic coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global concern. Environmental factors such as air pollution and smoking and comorbid conditions (hypertension, diabetes mellitus and underlying cardio-respiratory illness) likely increase the severity of COVID-19. Rheumatic manifestations such as arthralgias and arthritis may be prevalent in about a seventh of individuals. COVID-19 can result in acute interstitial pneumonia, myocarditis, leucopenia (with lymphopenia) and thrombocytopenia, also seen in rheumatic diseases like lupus and Sjogren’s syndrome. Severe disease in a subset of patients may be driven by cytokine storm, possibly due to secondary hemophagocytic lymphohistiocytosis (HLH), akin to that in systemic onset juvenile idiopathic arthritis or adult-onset Still’s disease. In the absence of high-quality evidence in this emerging disease, understanding of pathogenesis may help postulate potential therapies. Angiotensin converting enzyme 2 (ACE2) appears important for viral entry into pneumocytes; dysbalance in ACE2 as caused by ACE inhibitors or ibuprofen may predispose to severe disease. Preliminary evidence suggests potential benefit with chloroquine or hydroxychloroquine. Antiviral drugs like lopinavir/ritonavir, favipiravir and remdesivir are also being explored. Cytokine storm and secondary HLH might require heightened immunosuppressive regimens. Current international society recommendations suggest that patients with rheumatic diseases on immunosuppressive therapy should not stop glucocorticoids during COVID-19 infection, although minimum possible doses may be used. Disease-modifying drugs should be continued; cessation may be considered during infection episodes as per standard practices. Development of a vaccine may be the only effective long-term protection against this disease.

Title: [Therapy of coronavirus disease 2019 induced acute respiratory distress syndrome is different from traditional acute respiratory distress syndrome] Content: Coronavirus disease 2019 (COVID-19) has become a global public health emergency threatening people's lives around the world. Although the acute respiratory distress syndrome (ARDS) induced by COVID-19 is similar to the ARDS caused by other diseases in terms of pathophysiological basis and clinical manifestations, they are also different in many aspects, which lead to different clinical therapies. Therefore, understanding the differences and similarities of ARDS induced by COVID-19 and other diseases currently are the basis for clinicians to make decisions for the treatment of COVID-19 induced ARDS.

Title: [Therapy of coronavirus disease 2019 induced acute respiratory distress syndrome is different from traditional acute respiratory distress syndrome]. Content: Coronavirus disease 2019 (COVID-19) has become a global public health emergency threatening people's lives around the world. Although the acute respiratory distress syndrome (ARDS) induced by COVID-19 is similar to the ARDS caused by other diseases in terms of pathophysiological basis and clinical manifestations, they are also different in many aspects, which lead to different clinical therapies. Therefore, understanding the differences and similarities of ARDS induced by COVID-19 and other diseases currently are the basis for clinicians to make decisions for the treatment of COVID-19 induced ARDS.

Title: Histopathology and genetic susceptibility in COVID‐19 pneumonia Content: The clinical features of COVID‐19 range from a mild illness to patients with a very severe illness with acute hypoxemic respiratory failure requiring ventilation and Intensive Care Unit admission. Risk factors for a fatal disease include older age, respiratory disease, diabetes mellitus, obesity and hypertension. Little is known about the mechanisms behind observed episodes of sudden deterioration or the infrequent idiosyncratic clinical demise in otherwise healthy and young subjects. As in other diseases, the answer to some of these questions may in time be provided by genotyping as well careful clinical, serological, radiological and histopathological phenotyping, which enable mechanistic insights into the differences in pathogenesis and underlying immunological and tissue regenerative response patterns. We will aim to provide a brief overview of the existing evidence for such differences in host response and outcome, and generate hypotheses for divergent patterns and avenues for future research, by highlighting similarities and differences in histopathological appearance between COVID19 and influenza as well as previous coronavirus outbreaks, and by discussing predisposition through genetics and underlying disease.

Title: COVID-19 - Toward a comprehensive understanding of the disease Content: The evidence on the pathophysiology of the novel coronavirus SARS-CoV-2 infection is rapidly growing. Understanding why some patients suffering from COVID-19 are getting so sick, while others are not, has become an informal imperative for researchers and clinicians around the globe. The answer to this question would allow rationalizing the fear surrounding this pandemic. Understanding of the pathophysiology of COVID-19 relies on an understanding of interplaying mechanisms, including SARS-CoV-2 virulence, human immune response, and complex inflammatory reactions with coagulation playing a major role. An interplay with bacterial co-infections, as well as the vascular system and microcirculation affected throughout the body should also be examined. More importantly, a compre-hensive understanding of pathological mechanisms of COVID-19 will increase the efficacy of therapy and decrease mortality. Herewith, presented is the current state of knowledge on COVID-19: beginning from the virus, its transmission, and mechanisms of entry into the human body, through the pathological effects on the cellular level, up to immunological reaction, systemic and organ presentation. Last but not least, currently available and possible future therapeutic and diagnostic options are briefly commented on.

Title: COVID-19 Pandemic: Is Chronic Inflammation a Major Cause of Death? Content: Abstract Background. Today humanity is facing another infectious threat: a newly emerging virus SARS-CoV-2 causing COVID-19. It was already described that COVID-19 mortality among elderly people and people with such underlying conditions as obesity, cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes s increased. Dysregulation of the immune responses vital for antiviral defense, which are typical for chronic inflammation, led us to a hypothesis that chronic inflammation is the main risk factor for increased susceptibility and mortality from COVID-19. Method. Based on the available information for 126 countries, statistical analysis to find out whether the difference in incidence and mortality within countries can be explained by the existing chronic inflammation among the countries population, was conducted. Results. A positive correlation between the percentage of people dying from chronic noncommunicable diseases and COVID-19 incidence (p<0.001) and mortality (p<0.001) within countries. Conclusion. The problem of COVID-19-caused high mortality rate may be a consequence of the high number of people having chronic low-grade inflammation as a precondition, and thus, one of the potential ways to reduce risk of morbidity and mortality is to focus on this widespread health problem, mainly occurring in developed countries and to take corresponding diagnostic, preventative, and treatment measures.

Title: AhR and IDO1 in pathogenesis of Covid-19 and the "Systemic AhR Activation Syndrome:" Translational review and therapeutic perspectives Content: Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a "Systemic AhR Activation Syndrome" (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.

Title: AhR and IDO1 in pathogenesis of Covid-19 and the "Systemic AhR Activation Syndrome" Translational review and therapeutic perspectives. Content: Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a "Systemic AhR Activation Syndrome" (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.

Title: Innate Immunity in Coronavirus Infection ;врожденный Иммунитет При Коронавирусной Инфекции Content: Coronaviruses (CoVs) comprise a polymorphic group of respiratory viruses causing acute inflammatory diseases in domestic and agricultural animals (chicken, pig, buffalo, cat, dog) Until recently, this infection in humans was mainly observed during the autumn-winter period and characterized by a mild, often asymptomatic, course The situation changed dramatically in 2003, when SARS outbreak caused by pathogenic CoV (SARS-CoV) was recorded in China A decade later, a new CoV outbreak occurred in the form of the Middle East respiratory syndrome (MERS-CoV), whereas in December 2019, SARS-CoV-2 (COVID-19) cases were recorded, which transformed within the first months of 2020 into the pandemic In all three cases, CoV disease led to severe bronchopulmonary lesions, varying from dry, debilitating cough to acute respiratory distress syndrome (ARDS) At the same time, multiple changes in innate immunity were noted most often manifested as a pronounced inflammatory reaction in the lower respiratory tract, featured by damaged type II pneumocytes, apoptosis, hyalinization of alveolar membranes, focal or generalized pulmonary edema Destructive processes in the respiratory tract were accompanied by migration of monocytes/macrophages and granulocyte neutrophils to the inflammatory focus Such events were accompanied by production of pro-inflammatory cytokines, which magnitude could ascend up to a cytokine storm SARS-CoV is characterized by symptoms of secondary immunosuppression, manifested by the late onset of interferon production and activation of NLRP3 inflammasomes â€“ the key inflammatory factor The reason for such reaction may be accounted for by CoV arsenal containing extensive set of structural and inflammatory proteins exerting pro-inflammatory and immunosuppressive properties Delayed IFN production allowed CoV to replicate actively and freely, and when type I IFN synthesis was eventually triggered, its activity was detrimental and accompanied by an aggravated infection course Thus, SARS can surely be referred to immune-dependent infections with a marked immunopathological component The purpose of this review was to describe some mechanisms underlying formation of innate immune response to infection caused by pathogenic coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 (COVID-19) ;ÐšÐ¾Ñ€Ð¾Ð½Ð°Ð²Ð¸Ñ€ÑƒÑÑ‹ (CoV) Ð¿Ñ€ÐµÐ´ÑÑ‚Ð°Ð²Ð»ÑÑŽÑ‚ ÑÐ¾Ð±Ð¾Ð¹ Ð¿Ð¾Ð»Ð¸Ð¼Ð¾Ñ€Ñ„Ð½ÑƒÑŽ Ð³Ñ€ÑƒÐ¿Ð¿Ñƒ Ñ€ÐµÑÐ¿Ð¸Ñ€Ð°Ñ‚Ð¾Ñ€Ð½Ñ‹Ñ… Ð²Ð¸Ñ€ÑƒÑÐ¾Ð², Ð²Ñ‹Ð·Ñ‹Ð²Ð°ÑŽÑ‰Ð¸Ñ… Ð¾ÑÑ‚Ñ€Ñ‹Ðµ Ð²Ð¾ÑÐ¿Ð°Ð»Ð¸Ñ‚ÐµÐ»ÑŒÐ½Ñ‹Ðµ Ð·Ð°Ð±Ð¾Ð»ÐµÐ²Ð°Ð½Ð¸Ñ Ñƒ Ð´Ð¾Ð¼Ð°ÑˆÐ½Ð¸Ñ… Ð¸ ÑÐµÐ»ÑŒÑÐºÐ¾Ñ…Ð¾Ð·ÑÐ¹ÑÑ‚Ð²ÐµÐ½Ð½Ñ‹Ñ… Ð¶Ð¸Ð²Ð¾Ñ‚Ð½Ñ‹Ñ… (ÐºÑƒÑ€Ñ‹, ÑÐ²Ð¸Ð½ÑŒÐ¸, Ð±ÑƒÐ¹Ð²Ð¾Ð»Ñ‹, ÐºÐ¾ÑˆÐºÐ¸, ÑÐ¾Ð±Ð°ÐºÐ¸) Ð£ Ð»ÑŽÐ´ÐµÐ¹ Ð¸Ð½Ñ„ÐµÐºÑ†Ð¸Ñ Ð´Ð¾ Ð½ÐµÐ´Ð°Ð²Ð½ÐµÐ³Ð¾ Ð²Ñ€ÐµÐ¼ÐµÐ½Ð¸ Ð½Ð°Ð±Ð»ÑŽÐ´Ð°Ð»Ð¾ÑÑŒ Ð¿Ñ€ÐµÐ¸Ð¼ÑƒÑ‰ÐµÑÑ‚Ð²ÐµÐ½Ð½Ð¾ Ð² Ð¾ÑÐµÐ½Ð½Ðµ-Ð·Ð¸Ð¼Ð½Ð¸Ð¹ Ð¿ÐµÑ€Ð¸Ð¾Ð´ Ð¸ Ñ…Ð°Ñ€Ð°ÐºÑ‚ÐµÑ€Ð¸Ð·Ð¾Ð²Ð°Ð»Ð°ÑÑŒ Ð»ÐµÐ³ÐºÐ¸Ð¼, 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