Question: What is the mechanism of cytokine storm syndrome on the COVID-19?

Title: [Advances in the research of mechanism and related immunotherapy on the cytokine storm induced by coronavirus disease 2019] Content: Coronavirus disease 2019 (COVID-19) has seriously affected the safety of patients and social stability. Some COVID-19 patients in the later stage of disease may develop into acute respiratory distress syndrome or even multiple organ failure. However, one of the most important mechanisms underlying the deterioration of disease is cytokine storm. At present, some therapies such as interleukin-6 antibody blocker, stem cell therapy, and transfusion of convalescent plasma have been applied to counteract the cytokine storm with some progresses being achieved. This article reviews the influences of cytokine storm syndrome on the COVID-19 and the corresponding immunotherapies to resist cytokine storm.

Title: [Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies] Content: Corona Virus Disease 2019 (COVID-19) has seriously affected the treatment of patients and social stability. In the later stage of disease, some COVID-19 patients may develop into acute respiratory distress syndrome or even multiple organ failure. However, one of the most important mechanism underlying the deterioration of disease is cytokine storm. At present, some therapies such as interleukin-6 antibody blocker, stem cell therapy, and transfusion of convalescent plasma have been applied to counteract the cytokine storm and have made some progress. This article reviews the influences of cytokine storm syndrome on the COVID-19 and the corresponding immunotherapies to resist cytokine storm.

Title: [Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies]. Content: Corona Virus Disease 2019 (COVID-19) has seriously affected the treatment of patients and social stability. In the later stage of disease, some COVID-19 patients may develop into acute respiratory distress syndrome or even multiple organ failure. However, one of the most important mechanism underlying the deterioration of disease is cytokine storm. At present, some therapies such as interleukin-6 antibody blocker, stem cell therapy, and transfusion of convalescent plasma have been applied to counteract the cytokine storm and have made some progress. This article reviews the influences of cytokine storm syndrome on the COVID-19 and the corresponding immunotherapies to resist cytokine storm.

Title: Treatment of Severe COVID-19 with Tocilizumab Mitigates Cytokine Storm and Averts Mechanical Ventilation During Acute Respiratory Distress: A Case Report and Literature Review Content: COVID-19, caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2), emerged in Wuhan, China, in 2019 and has resulted in the current pandemic The disease continues to pose a major therapeutic challenge Patient mortality is ultimately caused by acute respiratory distress syndrome (ARDS) Cytokine release syndrome (or "cytokine storm") is likely to be a contributing factor to ARDS in many patients Because interleukin 6 (IL-6) is known to play a key role in inflammation, IL-6 receptor inhibitors such as tocilizumab may potentially treat COVID-19 by attenuating cytokine release We present the case of a 48-year-old male with severe COVID-19, on the verge of meeting intubation requirements, who needed progressive oxygen support for respiratory distress The patient was treated with a non-weight-based dosage of tocilizumab to prevent the onset of a cytokine storm We chose to administer an IL-6 inhibitor because of the gradually increasing levels of acute phase reactants identified on serial blood draws, as well as his declining respiratory status The treatment was well-tolerated in conjunction with standard drug therapies for COVID-19 (hydroxychloroquine, azithromycin, and zinc) The patient subsequently experienced marked improvements in his respiratory symptoms and overall clinical status over the following days We believe that tocilizumab played a substantial role in his ability to avert clinical decline, particularly the need for mechanical ventilation Ultimately, the patient was downgraded from the ICU and discharged within days We highlight the potential of IL-6 inhibitors to prevent the progression of respiratory disease to a point requiring ventilator support This case underscores the potential importance of early serial measurements of IL-6 and cytokine storm-associated acute phase reactants, such as ferritin, D-dimer, and C-reactive protein, in guiding clinical decision-making in the management of patients with suspected COVID-19 Conclusion: The early, proactive identification of serum acute phase reactants should be implemented in the treatment of COVID-19 in order to screen for a primary contributor to mortality-the cytokine storm This screening, when followed by aggressive early treatment for cytokine storm, may have optimal therapeutic benefits and obviate the need for mechanical ventilation, thereby decreasing mortality Additionally, we review current evidence regarding cytokine release syndrome in COVID-19 and the use of IL-6 receptor inhibition as a therapeutic strategy, and examine other reported cases in the literature describing IL-6 antagonist treatment for patients with COVID-19

Title: The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging” Content: PURPOSE: Novel Coronavirus disease 2019 (COVID-19), is an acute respiratory distress syndrome (ARDS), which is emerged in Wuhan, and recently become worldwide pandemic. Strangely, ample evidences have been shown that the severity of COVID-19 infections varies widely from children (asymptomatic), adults (mild infection), as well as elderly adults (deadly critical). It has proven that COVID-19 infection in some elderly critical adults leads to a cytokine storm, which is characterized by severe systemic elevation of several pro-inflammatory cytokines. Then, a cytokine storm can induce edematous, ARDS, pneumonia, as well as multiple organ failure in aged patients. It is far from clear till now why cytokine storm induces in only COVID-19 elderly patients, and not in young patients. However, it seems that aging is associated with mild elevated levels of local and systemic pro-inflammatory cytokines, which is characterized by “inflamm-aging”. It is highly likely that “inflamm-aging” is correlated to increased risk of a cytokine storm in some critical elderly patients with COVID-19 infection. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for COVID-19, Coronavirus, SARS-CoV-2, senescent cell, cytokine storm, inflame-aging, ACE2 receptor, autophagy, and Vitamin D. Electronic database searches combined and duplicates were removed. RESULTS: The aim of the present review was to summarize experimental data and clinical observations that linked the pathophysiology mechanisms of “inflamm-aging”, mild-grade inflammation, and cytokine storm in some elderly adults with severe COVID-19 infection.

Title: The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of "inflame-aging" Content: PURPOSE: Novel Coronavirus disease 2019 (COVID-19), is an acute respiratory distress syndrome (ARDS), which is emerged in Wuhan, and recently become worldwide pandemic. Strangely, ample evidences have been shown that the severity of COVID-19 infections varies widely from children (asymptomatic), adults (mild infection), as well as elderly adults (deadly critical). It has proven that COVID-19 infection in some elderly critical adults leads to a cytokine storm, which is characterized by severe systemic elevation of several pro-inflammatory cytokines. Then, a cytokine storm can induce edematous, ARDS, pneumonia, as well as multiple organ failure in aged patients. It is far from clear till now why cytokine storm induces in only COVID-19 elderly patients, and not in young patients. However, it seems that aging is associated with mild elevated levels of local and systemic pro-inflammatory cytokines, which is characterized by "inflamm-aging". It is highly likely that "inflamm-aging" is correlated to increased risk of a cytokine storm in some critical elderly patients with COVID-19 infection. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for COVID-19, Coronavirus, SARS-CoV-2, senescent cell, cytokine storm, inflame-aging, ACE2 receptor, autophagy, and Vitamin D. Electronic database searches combined and duplicates were removed. RESULTS: The aim of the present review was to summarize experimental data and clinical observations that linked the pathophysiology mechanisms of "inflamm-aging", mild-grade inflammation, and cytokine storm in some elderly adults with severe COVID-19 infection.

Title: Tocilizumab: A Therapeutic Option for the Treatment of Cytokine Storm Syndrome in COVID-19 Content: Abstract Presently, we need more therapeutic molecules for this COVID-19 outbreak. The severity and mortality of the disease is associated with a high level of release of cytokine in the patients which is known as CRS (cytokine release syndrome) or cytokine storm syndrome. IL-6 is a type of pro-inflammatory cytokine which release in the severe COVID-19 patients. This cytokine initiates CRS the JAK-STAT pathway. Tocilizumab, a humanized monoclonal antibody, is designed to bind both mIL-6R (membrane bound receptor for IL-6) and sIL-6R (soluble receptor for IL-6) and inhibit the JAK-STAT signaling pathway. It finally stops the cytokine storm syndrome. However, we need to understand that how tocilizumab is bound with mIL-6R or sIL-6R. Similarly, we also need to understand more about the real molecular mechanism of activity of tocilizumab.

Title: Rational Use of Tocilizumab in the Treatment of Novel Coronavirus Pneumonia Content: Since December 2019, a novel coronavirus pneumonia (COVID-19) has broken out in Wuhan, China and spread rapidly. Recent studies have found that ⁓ 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. IL-6 is one of the key cytokines involved in infection-induced cytokine storm. Tocilizumab, which is the IL-6 receptor antagonist, has been approved by the US FDA for the treatment of cytokine release syndrome (CRS), is expected to treat cytokine storm caused by COVID-19 and is now in clinical trials. In this paper, we will elaborate the role of cytokine storm in COVID-19, the mechanism of tocilizumab on cytokine storm and the key points of pharmaceutical care based on the actual clinical application for COVID-19 in our hospital, the latest research reports, clinical trial progress of tocilizumab, drug instruction from the US FDA, and “Diagnosis and Treatment Plan of Novel Coronavirus Pneumonia (seventh trial edition)” in China, so as to provide reference for the treatment of COVID-19.

Title: Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment Content: COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.

Title: Cytokine Storm Induced by SARS-CoV-2 Content: A novel coronavirus disease 2019 (COVID-19) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently spreading globally, causing severe pneumonia and acute lung injury in many patients. Even worse, severe respiratory may develop into acute respiratory distress syndrome and multiple organ dysfunction syndrome in COVID-19. The cytokine storm caused by immune over-activation due to virus infection may be an important cause of death in the late period of progress, but the pathogenesis of cytokine storm is still unclear. This article reviews the mechanisms of SARS-CoV-2-induced cytokine storm in detail based on the current discovered researches, and put forward some valuable medication ideas for the targeted cytokines drug researches and treatment. The goal of this work will be helpful for reducing excessive immune response.

Title: Rational Use of Tocilizumab in the Treatment of Novel Coronavirus Pneumonia Content: Since December 2019, a novel coronavirus pneumonia (COVID-19) has broken out in Wuhan, China and spread rapidly. Recent studies have found that â 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. IL-6 is one of the key cytokines involved in infection-induced cytokine storm. Tocilizumab, which is the IL-6 receptor antagonist, has been approved by the US FDA for the treatment of cytokine release syndrome (CRS), is expected to treat cytokine storm caused by COVID-19 and is now in clinical trials. In this paper, we will elaborate the role of cytokine storm in COVID-19, the mechanism of tocilizumab on cytokine storm and the key points of pharmaceutical care based on the actual clinical application for COVID-19 in our hospital, the latest research reports, clinical trial progress of tocilizumab, drug instruction from the US FDA, and "Diagnosis and Treatment Plan of Novel Coronavirus Pneumonia (seventh trial edition)" in China, so as to provide reference for the treatment of 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: 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: The cytokine storm and COVID-19 Content: Coronavirus disease 2019 (COVID-19), which began in Wuhan, China in December 2019 has caused a large global pandemic and poses a serious threat to public health. More than four million cases of COVID-19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been confirmed as of May 11, 2020. SARS-CoV-2 is a highly pathogenic and transmissible coronavirus that primarily spreads through respiratory droplets and close contact. A growing body of clinical data suggests that a cytokine storm is associated with COVID-19 severity and is also a crucial cause of death from COVID-19. In the absence of antivirals and vaccines for COVID-19, there is an urgent need to understand the cytokine storm in COVID-19. Here, we have reviewed the current understanding of the features of SARS-CoV-2 and the pathological features, pathophysiological mechanisms, and treatments of the cytokine storm induced by COVID-19. Additionally, we suggest that the identification and treatment of the cytokine storm are important components for rescuing patients with severe COVID-19. This article is protected by copyright. All rights reserved.

Title: The cytokine storm and COVID‐19 Content: Coronavirus disease 2019 (COVID‐19), which began in Wuhan, China in December 2019 has caused a large global pandemic and poses a serious threat to public health. More than four million cases of COVID‐19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), have been confirmed as of May 11, 2020. SARS‐CoV‐2 is a highly pathogenic and transmissible coronavirus that primarily spreads through respiratory droplets and close contact. A growing body of clinical data suggests that a cytokine storm is associated with COVID‐19 severity and is also a crucial cause of death from COVID‐19. In the absence of antivirals and vaccines for COVID‐19, there is an urgent need to understand the cytokine storm in COVID‐19. Here, we have reviewed the current understanding of the features of SARS‐CoV‐2 and the pathological features, pathophysiological mechanisms, and treatments of the cytokine storm induced by COVID‐19. Additionally, we suggest that the identification and treatment of the cytokine storm are important components for rescuing patients with severe COVID‐19. This article is protected by copyright. All rights reserved.

Title: Weather the Cytokine Storm: A Report of Successful Management of a Colon Cancer Survivor and a Critically Ill Patient with COVID-19 Content: Patients with novel corona virus infection (COVID-19) can develop acute respiratory failure secondary to acute respiratory distress syndrome. Cytokine storm is suggested as one of underlying mechanisms for the rapid clinical decline. Immunocompromised patients and cancer patients are at particular risk for poor outcomes due to COVID-19 infection. This case report describes the presentation and clinical course of a cancer survivor who became critically ill and required mechanical ventilation. The patient was treated with hydroxychloroquine, azithromycin, and ceftriaxone; however, he remained febrile, hypoxemic, continued to require full mechanical ventilator support and his chest X-ray showed increased bilateral infiltrates. The patient was treated with tocilizumab, after which he improved and was successfully extubated. This report illustrates a possible role of tocilizumab in management of cytokine storm in critically ill patients with COVID-19 infection.

Title: Cytokine storm induced by SARS-CoV-2 Content: Coronavirus disease 2019 (COVID-19), caused by the virus designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread widely throughout the world. Despite the strict global outbreak management and quarantine measures that have been implemented, the incidence of COVID-19 continues to rise, resulting in more than 290,000 deaths and representing an extremely serious threat to human life and health. The clinical symptoms of the affected patients are heterogeneous, ranging from mild upper respiratory symptoms to severe pneumonitis and even acute respiratory distress syndrome (ARDS) or death. Systemic immune over activation due to SARS-CoV-2 infection causes the cytokine storm, which is especially noteworthy in severely ill patients with COVID-19. Pieces of evidence from current studies have shown that the cytokine storm may be an important factor in disease progression, even leading to multiple organ failure and death. This review provides an overview of the knowledge on the COVID-19 epidemiological profile, the molecular mechanisms of the SARS-CoV-2-induced cytokine storm and immune responses, the pathophysiological changes that occur during infection, the main antiviral compounds used in treatment strategies and the potential drugs for targeting cytokines, this information is presented to provide valuable guidance for further studies and for a therapeutic reduction of this excessive immune response.

Title: Lung under attack by COVID-19-induced cytokine storm: pathogenic mechanisms and therapeutic implications Content: The lung is a key target of the cytokine storm that can be triggered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the widespread clinical syndrome known as coronavirus disease 2019 (COVID-19). Indeed, in some patients, SARS-CoV-2 promotes a dysfunctional immune response that dysregulates the cytokine secretory pattern. Hypercytokinemia underlies the hyperinflammatory state leading to injury of alveolar epithelial cells and vascular endothelial cells, as well as to lung infiltration sustained by neutrophils and macrophages. Within such a pathogenic context, interleukin-6 (IL-6) and other cytokines/chemokines play a pivotal pro-inflammatory role. Therefore, cytokines and their receptors, as well as cytokine-dependent intracellular signalling pathways can be targeted by potential therapies aimed to relieve the heavy burden of cytokine storm. In particular, the anti-IL-6-receptor monoclonal antibody tocilizumab is emerging as one of the most promising pharmacologic treatments. The reviews of this paper are available via the supplemental material section.

Title: Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19 Content: As a zoonotic disease that has already spread globally to several million human beings and possibly to domestic and wild animals, eradication of coronavirus disease 2019 (COVID-19) appears practically impossible. There is a pressing need to improve our understanding of the immunology of this disease to contain the pandemic by developing vaccines and medicines for the prevention and treatment of patients. In this review, we aim to improve our understanding on the immune response and immunopathological changes in patients linked to deteriorating clinical conditions such as cytokine storm, acute respiratory distress syndrome, autopsy findings and changes in acute-phase reactants, and serum biochemistry in COVID-19. Similar to many other viral infections, asymptomatic disease is present in a significant but currently unknown fraction of the affected individuals. In the majority of the patients, a 1-week, self-limiting viral respiratory disease typically occurs, which ends with the development of neutralizing antiviral T cell and antibody immunity. The IgM-, IgA-, and IgG-type virus-specific antibodies levels are important measurements to predict population immunity against this disease and whether cross-reactivity with other coronaviruses is taking place. High viral load during the first infection and repeated exposure to virus especially in healthcare workers can be an important factor for severity of disease. It should be noted that many aspects of severe patients are unique to COVID-19 and are rarely observed in other respiratory viral infections, such as severe lymphopenia and eosinopenia, extensive pneumonia and lung tissue damage, a cytokine storm leading to acute respiratory distress syndrome, and multiorgan failure. Lymphopenia causes a defect in antiviral and immune regulatory immunity. At the same time, a cytokine storm starts with extensive activation of cytokine-secreting cells with innate and adaptive immune mechanisms both of which contribute to a poor prognosis. Elevated levels of acute-phase reactants and lymphopenia are early predictors of high disease severity. Prevention of development to severe disease, cytokine storm, acute respiratory distress syndrome, and novel approaches to prevent their development will be main routes for future research areas. As we learn to live amidst the virus, understanding the immunology of the disease can assist in containing the pandemic and in developing vaccines and medicines to prevent and treat individual patients.

Title: Immune response to SARS‐CoV‐2 and mechanisms of immunopathological changes in COVID‐19 Content: As a zoonotic disease that has already spread globally to several million human beings and possibly to domestic and wild animals, eradication of coronavirus disease 2019 (COVID‐19) appears practically impossible. There is a pressing need to improve our understanding of the immunology of this disease to contain the pandemic by developing vaccines and medicines for the prevention and treatment of patients. In this review, we aim to improve our understanding on the immune response and immunopathological changes in patients linked to detoriating clinical conditions such as, cytokine storm, acute respiratory distress syndrome, autopsy findings and changes in acute phase reactants and serum biochemistry in COVID‐19. Similar to many other viral infections, asymptomatic disease is present in a significant but currently unknown fraction of the affected individuals.In the majority of the patients, a one‐week, self‐limiting viral respiratory disease typically occurs, which ends with the development of neutralizing anti‐viral T cell and antibody immunity. The IgM, IgA and IgG type virus‐specific antibodies levels are important measurements to predict population immunity against this disease and whether cross‐reactivity with other coronaviruses is taking place.High viral‐load during the first infection and repeated exposure to virus especially in healthcare workers can be an important factor for severity of disease. It should be noted that many aspects of severe patients are unique to COVID‐19 and are rarely observed in other respiratory viral infections, such as severe lymphopenia and eosinopenia, extensive pneumonia and lung tissue damage, a cytokine storm leading to acute respiratory distress syndrome and multiorgan failure. Lymphopenia causes a defect in antiviral and immune regulatory immunity. At the same time, a cytokine storm starts with extensive activation of cytokine‐secreting cells with innate and adaptive immune mechanisms both of with contribute to a poor prognosis. Elevated levels of acute phase reactants and lymphopenia are early predictors of high disease severity. Prevention of development to severe disease, cytokine storm, acute respiratory distress syndrome and novel approachs to prevent their development will be main routes for future research areas. As we learn to live amidst the virus, understanding the immunology of the disease can assist in containing the pandemic and in developing vaccines and medicines to prevent and treat individual 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: Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts Content: Clinical evidence indicates that the fatal outcome observed with severe acute respiratory syndrome-coronavirus-2 infection often results from alveolar injury that impedes airway capacity and multi-organ failure-both of which are associated with the hyperproduction of cytokines, also known as a cytokine storm or cytokine release syndrome. Clinical reports show that both mild and severe forms of disease result in changes in circulating leukocyte subsets and cytokine secretion, particularly IL-6, IL-1ß, IL-10, TNF, GM-CSF, IP-10 (IFN-induced protein 10), IL-17, MCP-3, and IL-1ra. Not surprising, therapies that target the immune response and curtail the cytokine storm in coronavirus 2019 (COVID-19) patients have become a focus of recent clinical trials. Here we review reports on leukocyte and cytokine data associated with COVID-19 disease in 3939 patients in China and describe emerging data on immunopathology. With an emphasis on immune modulation, we also look at ongoing clinical studies aimed at blocking proinflammatory cytokines; transfer of immunosuppressive mesenchymal stem cells; use of convalescent plasma transfusion; as well as immunoregulatory therapy and traditional Chinese medicine regimes. In examining leukocyte and cytokine activity in COVID-19, we focus in particular on how these levels are altered as the disease progresses (neutrophil NETosis, macrophage, T cell response, etc.) and proposed consequences to organ pathology (coagulopathy, etc.). Viral and host interactions are described to gain further insight into leukocyte biology and how dysregulated cytokine responses lead to disease and/or organ damage. By better understanding the mechanisms that drive the intensity of a cytokine storm, we can tailor treatment strategies at specific disease stages and improve our response to this worldwide public health threat.

Title: Cytokine storm and leukocyte changes in mild versus severe SARS‐CoV‐2 infection: Review of 3939 COVID‐19 patients in China and emerging pathogenesis and therapy concepts Content: Clinical evidence indicates that the fatal outcome observed with severe acute respiratory syndrome‐coronavirus‐2 infection often results from alveolar injury that impedes airway capacity and multi‐organ failure—both of which are associated with the hyperproduction of cytokines, also known as a cytokine storm or cytokine release syndrome. Clinical reports show that both mild and severe forms of disease result in changes in circulating leukocyte subsets and cytokine secretion, particularly IL‐6, IL‐1β, IL‐10, TNF, GM‐CSF, IP‐10 (IFN‐induced protein 10), IL‐17, MCP‐3, and IL‐1ra. Not surprising, therapies that target the immune response and curtail the cytokine storm in coronavirus 2019 (COVID‐19) patients have become a focus of recent clinical trials. Here we review reports on leukocyte and cytokine data associated with COVID‐19 disease in 3939 patients in China and describe emerging data on immunopathology. With an emphasis on immune modulation, we also look at ongoing clinical studies aimed at blocking proinflammatory cytokines; transfer of immunosuppressive mesenchymal stem cells; use of convalescent plasma transfusion; as well as immunoregulatory therapy and traditional Chinese medicine regimes. In examining leukocyte and cytokine activity in COVID‐19, we focus in particular on how these levels are altered as the disease progresses (neutrophil NETosis, macrophage, T cell response, etc.) and proposed consequences to organ pathology (coagulopathy, etc.). Viral and host interactions are described to gain further insight into leukocyte biology and how dysregulated cytokine responses lead to disease and/or organ damage. By better understanding the mechanisms that drive the intensity of a cytokine storm, we can tailor treatment strategies at specific disease stages and improve our response to this worldwide public health threat.

Title: Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19 Content: In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1-2 weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19.

Title: Traditional Chinese medicine for treatment of COVID-19 based on literature mining of targeting cytokine storm/ 基于干预细胞因子风暴文献挖掘的中医药治疗重症新型冠状病毒肺炎探讨 Content: The primary clinical manifestations of coronavirus disease 2019 (COVID-19) are fever, fatigue and dry cough. Several clinical studies reported that some patients with low or medium fever, or even without obvious symptom, rapidly progressed to severe or critical illness, including severe acute respiratory syndrome, septic shock, coagulation disorders and intractable metabolic acidosis. These patients were usually associated with significant elevated serum levels of a profile of cytokines, which is similar to SARS-2003 and MERS-2015, indicating the occurrence of cytokine storm. In the present review, we summarized previous advances in the treatment of severe cases of SARS by using traditional Chinese medicines (TCM), especially those TCM targeting cytokine storm, based on literature mining. By using data mining and network pharmacology, we also investigated underlying mechanisms and biological pathways involved in the inhibitory effects of TCM against cytokine storm. This review not only provides novel insights in the precise application of TCM, appropriate integrative use of TCM in combination with western medicine, but also contributes to the discovery of novel drugs or new therapeutic strategies targeting cytokine storm to suppress progression of COVID-19 and to improve clinical prognosis and outcomes.

Title: Weathering the Cytokine Storm in COVID-19: Therapeutic Implications Content: BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged in Wuhan, Hubei-China, as responsible for the coronavirus disease 2019 (COVID-19) and then spread rapidly worldwide. While most individuals remain asymptomatic or develop only mild symptoms, approximately 5% develop severe forms of COVID-19 characterized by acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF) that usually require intensive-care support and often yield a poor prognosis. SUMMARY: The pathophysiology of COVID-19 is far from being completely understood, and the lack of effective treatments leads to a sense of urgency to develop new therapeutic strategies based on pathophysiological assumptions. The exaggerated cytokine release in response to viral infection, a condition known as cytokine release syndrome (CRS) or cytokine storm, is emerging as the mechanism leading to ARDS and MOF in COVID-19, thus endorsing the hypothesis that properly timed anti-inflammatory therapeutic strategies could improve patients' clinical outcomes and prognosis. KEY MESSAGES: The objective of this article is to explore and comment on the potential role of the promising immunomodulatory therapies using pharmacological and nonpharmacological approaches to overcome the dysregulated proinflammatory response in COVID-19.

Title: Weathering the Cytokine Storm in COVID-19: Therapeutic Implications Content: BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged in Wuhan, Hubei-China, as responsible for the coronavirus disease 2019 (COVID-19) and then spread rapidly worldwide. While most individuals remain asymptomatic or develop only mild symptoms, approximately 5% develop severe forms of COVID-19 characterized by acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF) that usually require intensive-care support and often yield a poor prognosis. SUMMARY: The pathophysiology of COVID-19 is far from being completely understood, and the lack of effective treatments leads to a sense of urgency to develop new therapeutic strategies based on pathophysiological assumptions. The exaggerated cytokine release in response to viral infection, a condition known as cytokine release syndrome (CRS) or cytokine storm, is emerging as the mechanism leading to ARDS and MOF in COVID-19, thus endorsing the hypothesis that properly timed anti-inflammatory therapeutic strategies could improve patients' clinical outcomes and prognosis. Key Messages: The objective of this article is to explore and comment on the potential role of the promising immunomodulatory therapies using pharmacological and nonpharmacological approaches to overcome the dysregulated proinflammatory response in COVID-19.

Title: Potential for jaktinib hydrochloride to treat cytokine storms in patients with COVID-19 Content: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a serious public health threat to the whole world, and the number of infected is still rising dramatically at this moment. Several studies have confirmed that cytokine storms play a critical role in causing a case to worsen from mild to severe or critical. The current treatment for cytokine storms is limited, so the international medical community is focusing on a specific and effective remedy. Jaktinib hydrochloride is a broad spectrum JAK inhibitor. It can inhibit cytokine-induced immune activation by multiple mechanisms and also slow viral proliferation by inhibiting AAK1 without causing unacceptable toxicity. Jaktinib hydrochloride has great potential for the treatment of patients with coronavirus disease 2019 (COVID-19).

Title: Potential for jaktinib hydrochloride to treat cytokine storms in patients with COVID-19. Content: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a serious public health threat to the whole world, and the number of infected is still rising dramatically at this moment. Several studies have confirmed that cytokine storms play a critical role in causing a case to worsen from mild to severe or critical. The current treatment for cytokine storms is limited, so the international medical community is focusing on a specific and effective remedy. Jaktinib hydrochloride is a broad spectrum JAK inhibitor. It can inhibit cytokine-induced immune activation by multiple mechanisms and also slow viral proliferation by inhibiting AAK1 without causing unacceptable toxicity. Jaktinib hydrochloride has great potential for the treatment of patients with coronavirus disease 2019 (COVID-19).

Title: Pirfenidone: A novel hypothetical treatment for COVID-19 Content: Cytokine storm, multiorgan failure, and particularly acute respiratory distress syndrome (ARDS) is the leading cause of mortality and morbidity in patients with COVID-19. A fulminant ARDS kills the majority of COVID-19 victims. Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), is a novel anti-fibrotic agent with trivial adverse effects. Pirfenidone is approved for the treatment of Idiopathic Pulmonary Fibrosis (IPF) for patients with mild to moderate disease. Pirfenidone could inhibit apoptosis, downregulate ACE receptors expression, decrease inflammation by several mechanisms and ameliorate oxidative stress and hence protect pneumocytes and other cells from COVID-19 invasion and cytokine storm simultaneously. Based on the pirfenidone mechanism of action and the known pathophysiology of COVID-19, I believe that pirfenidone has the potential for the treatment of COVID-19 patients.

Title: COVID-19: Consider IL-6 receptor antagonist for the therapy of cytokine storm syndrome in SARS-CoV-2 infected patients Content: COVID-19 leads to mortality of several patients and the cytokine storm is reportedly critical in the patients. To reduce the cytokine storm, we would like to propose the interleukin (IL) 6 receptor (IL-6R) antagonist therapy for the COVID-19 patients. Two humanized monoclonal antibodies are in clinical trial following IL-6R antagonist therapies namely tocilizumab and sarilumab. However, researchers and physicians should look for more IL-6R antagonists for the therapy of cytokine storm syndrome severe acute respiratory syndrome coronavirus 2 infected persons to enhance the therapeutic options for cytokine storm.

Title: Recovery of COVID-19 acute respiratory distress syndrome with tocilizumab: successful outcome in two critically ill patients Content: Background: Severe pneumonia and acute respiratory distress syndrome (ARDS) due to COVID-19 is a challenge for nowadays medical practice. Although there is no clarity in the principal mechanism of lung damage and ARDS development, it has been suggested that one of the main reasons of this pathology is the hyperactivation of the immune system, better known as cytokine storm syndrome. Tocilizumab has been proposed to treat COVID-19 severe cases associated to ARDS. Results & methodology: Here we present two successful cases of tocilizumab administration in two COVID-19 patients with prior administration of antiviral therapy (hydroxychloroquine, azithromycin, lopinavir and ritonavir) with adequate response and resolution of ARDS, septic shock and severe pneumonia within the first 72 h. Discussion & conclusion: This case supports the usage of tocilizumab as an effective therapy in COVID-19 associated cytokine storm syndrome. Further studies should be done in order to assess its effectiveness and security.

Title: Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19 Content: Importance: Coronavirus disease 2019 (COVID-19) is a pandemic with no specific drugs and high mortality. The most urgent thing is to find effective treatments. Objective: To determine whether hydroxychloroquine application may be associated with a decreased risk of death in critically ill COVID-19 patients and what is potential mechanism. Design, Setting and Patients: This retrospective study included all 568 critically ill COVID-19 patients who were confirmed by pathogen laboratory tests despite antiviral treatment and had severe acute respiratory distress syndrome, PAO2/FIO2 <300 with need of mechanical ventilation in Tongji Hospital, Wuhan, between February 1 of 2020 to April 8 of 2020. All 568 patients received comparable basic treatments including antiviral drugs and antibiotics, and 48 of them additionally received oral hydroxychloroquine (HCQ) treatment (200 mg twice a day for 7-10 days). Primary endpoint is mortality of patients, and inflammatory cytokines levels were compared between hydroxychloroquine and non-hydroxychloroquine (NHCQ) treatments. MAIN OUTCOMES AND MEASURES: In-hospital death and hospital stay time (day) were obtained, level of inflammatory cytokine (IL-6) was measured and compared between HCQ and NHCQ treatments. RESULTS: The median age of 568 critically ill patients is 68 (57, 76) years old with 37.0% being female. Mortalities are 18.8% (9/48) in HCQ group and 45.8% (238/520) in NHCQ group (p<0.001). The time of hospital stay before patient death is 15 (10-21) days and 8 (4 - 14) days for the HCQ and NHCQ groups, respectively (p<0.05). The level of inflammatory cytokine IL-6 was significantly lowered from 22.2 (8.3-118.9) pg/mL at the beginning of the treatment to 5.2 (3.0-23.4) pg/ml (p<0.05) at the end of the treatment in the HCQ group but there is no change in the NHCQ group. CONCLUSIONS AND RELEVANCE: Hydroxychloroquine treatment is significantly associated with a decreased mortality in critically ill patients with COVID-19 through attenuation of inflammatory cytokine storm. Therefore, hydroxychloroquine should be prescribed for treatment of critically ill COVID-19 patients to save lives.

Title: COVID‐19: Consider IL6 receptor antagonist for the therapy of cytokine storm syndrome in SARS‐CoV‐2 infected patients Content: COVID‐19 leads to mortality of several patients and the cytokine storm is reportedly critical in the patients. In order to reduce the cytokine storm, we would like to propose the IL6 receptor antagonist therapy for the COVID‐19 patients. Two humanized monoclonal antibodies are in clinical trial following IL6R antagonist therapies namely tocilizumab and sarilumab. However, researchers and physicians should look for more IL6 receptor antagonists for the therapy of cytokine storm syndrome SARS‐CoV‐2 infected persons to enhance the therapeutic options for cytokine storm. This article is protected by copyright. All rights reserved.

Title: Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients. Content: COVID-19, the illness caused by infection with the novel coronavirus SARS-CoV-2, is a rapidly spreading global pandemic in urgent need of effective treatments. Here we present a comprehensive examination of the host- and virus-targeted functions of the flavonolignan silibinin, a potential drug candidate against COVID-19/SARS-CoV-2. As a direct inhibitor of STAT3-a master checkpoint regulator of inflammatory cytokine signaling and immune response-silibinin might be expected to phenotypically integrate the mechanisms of action of IL-6-targeted monoclonal antibodies and pan-JAK1/2 inhibitors to limit the cytokine storm and T-cell lymphopenia in the clinical setting of severe COVID-19. As a computationally predicted, remdesivir-like inhibitor of RNA-dependent RNA polymerase (RdRp)-the central component of the replication/transcription machinery of SARS-CoV-2-silibinin is expected to reduce viral load and impede delayed interferon responses. The dual ability of silibinin to target both the host cytokine storm and the virus replication machinery provides a strong rationale for the clinical testing of silibinin against the COVID-19 global public health emergency. A randomized, open-label, phase II multicentric clinical trial (SIL-COVID19) will evaluate the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome in moderate-to-severe COVID-19-positive onco-hematological patients at the Catalan Institute of Oncology in Catalonia, Spain.

Title: On the Alert for Cytokine Storm: Immunopathology in COVID-19 Content: Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.

Title: On the Alert for Cytokine Storm: Immunopathology in COVID‐19 Content: Poor outcomes in COVID‐19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID‐19.

Title: Favorable COVID-19 course despite significant comorbidities in a ruxolitinib-treated patient with primary myelofibrosis Content: COVID-19 carries a high risk of severe disease course, particularly in patients with comorbidities. Therapy of severe COVID-19 infection has relied on supportive intensive care measures. More specific approaches including drugs that limit the detrimental "cytokine storm", such as Janus-activated kinase (JAK) inhibitors, are being discussed. Here, we report a compelling case of a 55-yo patient with proven COVID-19 pneumonia, who was taking the JAK1/2 inhibitor ruxolitinib in-label for co-existing primary myelofibrosis for 15 months prior to coronavirus infection. The patient had significant comorbidities, including chronic kidney disease, arterial hypertension, and obesity, and our previous cohort suggested that he was thus at high risk for acute respiratory distress syndrome (ARDS) and death from COVID-19. Since abrupt discontinuation of ruxolitinib may cause fatal cytokine storm and ARDS, ruxolitinib treatment was continued and was well tolerated, and the patient´s condition remained stable, without the need for mechanical ventilation or vasopressors. The patient became negative for SARS-CoV-2 and was discharged home after 15 days. In conclusion, our report provides clinical evidence that ruxolitinib treatment is feasible and can be beneficial in patients with COVID-19 pneumonia, preventing cytokine storm and ARDS.

Title: Favorable COVID‐19 course despite significant comorbidities in a ruxolitinib‐treated patient with primary myelofibrosis Content: COVID‐19 carries a high risk of severe disease course, particularly in patients with comorbidities. Therapy of severe COVID‐19 infection has relied on supportive intensive care measures. More specific approaches including drugs that limit the detrimental “cytokine storm”, such as Janus‐activated kinase (JAK) inhibitors, are being discussed. Here, we report a compelling case of a 55‐yo patient with proven COVID‐19 pneumonia, who was taking the JAK1/2 inhibitor ruxolitinib in‐label for co‐existing primary myelofibrosis for 15 months prior to coronavirus infection. The patient had significant comorbidities, including chronic kidney disease, arterial hypertension, and obesity, and our previous cohort suggested that he was thus at high risk for acute respiratory distress syndrome (ARDS) and death from COVID‐19. Since abrupt discontinuation of ruxolitinib may cause fatal cytokine storm and ARDS, ruxolitinib treatment was continued and was well tolerated, and the patient´s condition remained stable, without the need for mechanical ventilation or vasopressors. The patient became negative for SARS‐CoV‐2 and was discharged home after 15 days. In conclusion, our report provides clinical evidence that ruxolitinib treatment is feasible and can be beneficial in patients with COVID‐19 pneumonia, preventing cytokine storm and ARDS.

Title: COVID-19 and the Heart Content: Infection with the severe acute respiratory syndrome novel coronavirus produces a clinical syndrome known as 2019 novel coronavirus disease (COVID-19). When severe, COVID-19 is a systemic illness characterized by hyperinflammation, cytokine storm, and elevations of cardiac injury biomarkers. Here, we review what is known about the pathophysiology of COVID-19, its cardiovascular manifestations, and emerging therapeutic prospects. In this rapidly moving field, this review was comprehensive as of April 3, 2020.

Title: The pathogenesis and treatment of the `Cytokine Storm' in COVID-19 Content: Summary Cytokine storm is an excessive immune response to external stimuli. The pathogenesis of the cytokine storm is complex. The disease progresses rapidly, and the mortality is high. Certain evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patients has been closely related to the cytokine storm in their bodies. This article reviews the occurrence mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in attempt to provide valuable medication guidance for clinical treatment.

Title: The pathogenesis and treatment of the `Cytokine Storm' in COVID-19 Content: Cytokine storm is an excessive immune response to external stimuli. The pathogenesis of the cytokine storm is complex. The disease progresses rapidly, and the mortality is high. Certain evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patients has been closely related to the cytokine storm in their bodies. This article reviews the occurrence mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in attempt to provide valuable medication guidance for clinical treatment.

Title: The amount of cytokine-release defines different shades of Sars-Cov2 infection. Content: The recent outbreak of coronavirus disease (COVID 19), spreading from China all around the world in early 2020, has led scientists to investigate the immuno-mediated mechanisms underlying the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection. Depending on the amount of cytokines released as the result of the immunological activation induced by SARS-CoV2, three major clinical phenotypes can be identified: "mild",symbolized as a "drizzle" of cytokines, severe as a "storm", and critical as a "hurricane". In patients with mild symptoms, the release of pro-inflammatory cytokines is balanced to obtain a defense response against the virus which is often self-limiting and overcomes without tissue damage. In severe phenotype, resembling a "cytokine-release syndrome", SARS-CoV2 causes the lysis of the immune-mediators leading to a cytokine storm able to induce lung epithelium damage and acute respiratory distress syndrome. In critical patients, the immune response may become uncontrolled, thus the cytokine burst resembles a form of secondary hemophagocytic lymphohistiocytosis which may result in a multi organ failure. In addition to the standard of care, an immune-modulatory therapy tailored to each one of the different phenotypes should be used in order to prevent or reduce the release of cytokines responsible for organ damage and disease progression.

Title: The amount of cytokine-release defines different shades of Sars-Cov2 infection Content: The recent outbreak of coronavirus disease (COVID 19), spreading from China all around the world in early 2020, has led scientists to investigate the immuno-mediated mechanisms underlying the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection. Depending on the amount of cytokines released as the result of the immunological activation induced by SARS-CoV2, three major clinical phenotypes can be identified: "mild",symbolized as a "drizzle" of cytokines, severe as a "storm", and critical as a "hurricane". In patients with mild symptoms, the release of pro-inflammatory cytokines is balanced to obtain a defense response against the virus which is often self-limiting and overcomes without tissue damage. In severe phenotype, resembling a "cytokine-release syndrome", SARS-CoV2 causes the lysis of the immune-mediators leading to a cytokine storm able to induce lung epithelium damage and acute respiratory distress syndrome. In critical patients, the immune response may become uncontrolled, thus the cytokine burst resembles a form of secondary hemophagocytic lymphohistiocytosis which may result in a multi organ failure. In addition to the standard of care, an immune-modulatory therapy tailored to each one of the different phenotypes should be used in order to prevent or reduce the release of cytokines responsible for organ damage and disease progression.

Title: Amelioration of COVID‐19 related cytokine storm syndrome: Parallels to chimeric antigen receptor‐T cell cytokine release syndrome Content: Coronavirus disease‐2019 (COVID‐19) severity appears to parallel the host immune response, with a subset of patients developing COVID‐19 cytokine storm syndrome (CSS).(1) Serum inflammatory cytokines are elevated in COVID‐19,(2–5) and interleukin (IL)‐6 appears to play a central role in COVID‐19 related CSS.(6–8) Based on the success of IL‐6 receptor blockade for chimeric antigen receptor T‐cell therapy associated cytokine release syndrome (CAR T‐cell CRS), similar strategies using tocilizumab are being investigated in COVID‐19.

Title: Amelioration of COVID-19 related cytokine storm syndrome: Parallels to chimeric antigen receptor-T cell cytokine release syndrome Content: Coronavirus disease-2019 (COVID-19) severity appears to parallel the host immune response, with a subset of patients developing COVID-19 cytokine storm syndrome (CSS).(1) Serum inflammatory cytokines are elevated in COVID-19,(2-5) and interleukin (IL)-6 appears to play a central role in COVID-19 related CSS.(6-8) Based on the success of IL-6 receptor blockade for chimeric antigen receptor T-cell therapy associated cytokine release syndrome (CAR T-cell CRS), similar strategies using tocilizumab are being investigated in COVID-19.

Title: Storm, typhoon, cyclone or hurricane in patients with COVID-19? Beware of the same storm that has a different origin Content: Some of the articles being published during the severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 pandemic highlight a link between severe forms of coronavirus disease 2019 (COVID-19) and the so-called cytokine storm, also with increased ferritin levels. However, this scenario is more complex than initially thought due to the heterogeneity of hyperinflammation. Some patients with coronavirus 2019 disease (COVID-19) develop a fully blown secondary haemophagocytic lymphohistiocytosis (sHLH), whereas others, despite a consistent release of pro-inflammatory cytokines, do not fulfil sHLH criteria but still show some features resembling the phenotype of the hyperferritinemic syndrome. Despite the final event (the cytokine storm) is shared by various conditions leading to sHLH, the aetiology, either infectious, autoimmune or neoplastic, accounts for the differences in the various phases of this process. Moreover, the evidence of a hyperinflammatory microenvironment provided the rationale to employ immunomodulating agents for therapeutic purposes in severe COVID-19. This viewpoint aims at discussing the pitfalls and issues to be considered with regard to the use of immunomodulating agents in COVID-19, such as timing of treatment based on the viral load and the extent of cytokine/ferritin overexpression. Furthermore, it encompasses recent findings in the paediatric field about a novel multisystem inflammatory disease resembling toxic shock syndrome and atypical Kawasaki disease observed in children with proven SARS-CoV2 infection. Finally, it includes arguments in favour of adding COVID-19 to the spectrum of the recently defined 'hyperferritinemic syndrome', which already includes adult-onset Still's disease, macrophage activation syndrome, septic shock and catastrophic anti-phospholipid syndrome.

Title: Storm, typhoon, cyclone or hurricane in patients with COVID-19? Beware of the same storm that has a different origin Content: Some of the articles being published during the severe acute respiratory syndrome–coronavirus (SARS-CoV)-2 pandemic highlight a link between severe forms of coronavirus disease 2019 (COVID-19) and the so-called cytokine storm, also with increased ferritin levels. However, this scenario is more complex than initially thought due to the heterogeneity of hyperinflammation. Some patients with coronavirus 2019 disease (COVID-19) develop a fully blown secondary haemophagocytic lymphohistiocytosis (sHLH), whereas others, despite a consistent release of pro-inflammatory cytokines, do not fulfil sHLH criteria but still show some features resembling the phenotype of the hyperferritinemic syndrome. Despite the final event (the cytokine storm) is shared by various conditions leading to sHLH, the aetiology, either infectious, autoimmune or neoplastic, accounts for the differences in the various phases of this process. Moreover, the evidence of a hyperinflammatory microenvironment provided the rationale to employ immunomodulating agents for therapeutic purposes in severe COVID-19. This viewpoint aims at discussing the pitfalls and issues to be considered with regard to the use of immunomodulating agents in COVID-19, such as timing of treatment based on the viral load and the extent of cytokine/ferritin overexpression. Furthermore, it encompasses recent findings in the paediatric field about a novel multisystem inflammatory disease resembling toxic shock syndrome and atypical Kawasaki disease observed in children with proven SARS-CoV2 infection. Finally, it includes arguments in favour of adding COVID-19 to the spectrum of the recently defined ‘hyperferritinemic syndrome’, which already includes adult-onset Still’s disease, macrophage activation syndrome, septic shock and catastrophic anti-phospholipid syndrome.

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: SARS-CoV-2: Viral Mechanisms and Possible Therapeutic Targets - What to learn from Rheumatologists? Content: It was with great interest that we read the letter from Randy Cron and collaborators (1) linking the cytokine storm syndrome (CSS) seen in macrophage activation syndrome, common in the rheumatological setting, with the CSS postulated to be a background in the novel coronavirus (SARS-CoV-2) infection. Amid the high contagiousness of the virus, science was also infected by an infodemia, compelled to enter a race to find effective therapies studying mechanisms molecular aspects of SARS-CoV-2 concomitant to urgent bedside manage of patients.

Title: Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic Content: Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, this clinical condition is considered as a cytokine storm syndrome. HPS has primary and acquired (secondary, reactive) forms. Its primary form is mostly seen in childhood and caused by various mutations with genetic inheritance and, therefore, is called familial HLH. Secondary HLH may be caused in the presence of an underlying disorder, that is, secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis and the clinical picture of HLH, and its severe complication, the cytokine storm, with a special emphasis on the developed classification criteria sets for rheumatologists, since COVID-19 infection has clinical symptoms resembling those of the common rheumatologic conditions and possibly triggers HLH. MED-LINE/Pubmed was searched from inception to April 2020, and the following terms were used for data searching: "hemophagocytic syndrome" OR "macrophage activation syndrome" OR "hemophagocytic lymphohistiocytosis", OR "cytokine storm". Finally, AND "COVID-19" was included in this algorithm. The selection is restricted to the past 5 years and limited numbers of earlier key references were manually selected. Only full-text manuscripts, published in an English language peer-reviewed journal were included. Manuscript selection procedure and numbers are given in Fig. 2. Briefly, the database search with the following terms of "Hemophagocytic syndrome" OR "Macrophage activation syndrome" OR "Hemophagocytic lymphohistiocytosis" OR "Cytokine storm" yielded 6744 results from inception to April 2020. The selection is restricted to the past 5 years and only limited numbers of earlier key references were selected, and this algorithm resulted in 3080 manuscripts. The addition of (AND "COVID-19") resulted in 115 publications of which 47 studies, together with four sections of an online book were used in the final review. No statistical method was used. HLH is triggered by genetic conditions, infections, malignancies, autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, secondary HLH and cytokine storm may be responsible for unexplained progressive fever, cytopenia, ARDS, neurological and renal impairment. Differentiation between the primary and secondary forms of HLH is utterly important, since primary form of HLH requires complicated treatments such as hematopoietic stem cell transplantation. Further studies addressing the performance of HScore and other recommendations in the classification of these patients is necessary.

Title: Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic Content: Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, this clinical condition is considered as a cytokine storm syndrome. HPS has primary and acquired (secondary, reactive) forms. Its primary form is mostly seen in childhood and caused by various mutations with genetic inheritance and, therefore, is called familial HLH. Secondary HLH may be caused in the presence of an underlying disorder, that is, secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis and the clinical picture of HLH, and its severe complication, the cytokine storm, with a special emphasis on the developed classification criteria sets for rheumatologists, since COVID-19 infection has clinical symptoms resembling those of the common rheumatologic conditions and possibly triggers HLH. MED-LINE/Pubmed was searched from inception to April 2020, and the following terms were used for data searching: “hemophagocytic syndrome” OR “macrophage activation syndrome” OR “hemophagocytic lymphohistiocytosis”, OR “cytokine storm”. Finally, AND “COVID-19” was included in this algorithm. The selection is restricted to the past 5 years and limited numbers of earlier key references were manually selected. Only full-text manuscripts, published in an English language peer-reviewed journal were included. Manuscript selection procedure and numbers are given in Fig. 2. Briefly, the database search with the following terms of “Hemophagocytic syndrome” OR “Macrophage activation syndrome” OR “Hemophagocytic lymphohistiocytosis” OR “Cytokine storm” yielded 6744 results from inception to April 2020. The selection is restricted to the past 5 years and only limited numbers of earlier key references were selected, and this algorithm resulted in 3080 manuscripts. The addition of (AND “COVID-19”) resulted in 115 publications of which 47 studies, together with four sections of an online book were used in the final review. No statistical method was used. HLH is triggered by genetic conditions, infections, malignancies, autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, secondary HLH and cytokine storm may be responsible for unexplained progressive fever, cytopenia, ARDS, neurological and renal impairment. Differentiation between the primary and secondary forms of HLH is utterly important, since primary form of HLH requires complicated treatments such as hematopoietic stem cell transplantation. Further studies addressing the performance of HScore and other recommendations in the classification of these patients is necessary.

Title: Severe COVID-19 and aging: are monocytes the key? Content: The ongoing pandemic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a disproportionate number of severe cases and deaths in older adults. Severe SARS-CoV-2-associated disease (coronavirus disease 2019 (COVID-19)) was declared a pandemic by the World Health Organization in March 2020 and is characterized by cytokine storm, acute respiratory distress syndrome, and in some cases by systemic inflammation–related pathology. Currently, our knowledge of the determinants of severe COVID-19 is primarily observational. Here, I review emerging evidence to argue that monocytes, a circulating innate immune cell, are principal players in cytokine storm and associated pathologies in COVID-19. I also describe changes in monocyte function and phenotype that are characteristic of both aging and severe COVID-19, which suggests a potential mechanism underlying increased morbidity and mortality due to SARS-CoV-2 infection in older adults. The innate immune system is therefore a potentially important target for therapeutic treatment of COVID-19, but experimental studies are needed, and SARS-CoV-2 presents unique challenges for pre-clinical and mechanistic studies in vivo. The immediate establishment of colonies of SARS-CoV-2-susceptible animal models for aging studies, as well as strong collaborative efforts in the geroscience community, will be required in order to develop the therapies needed to combat severe COVID-19 in older adult populations.

Title: Severe COVID-19 and aging: are monocytes the key? Content: The ongoing pandemic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a disproportionate number of severe cases and deaths in older adults. Severe SARS-CoV-2-associated disease (coronavirus disease 2019 (COVID-19)) was declared a pandemic by the World Health Organization in March 2020 and is characterized by cytokine storm, acute respiratory distress syndrome, and in some cases by systemic inflammation-related pathology. Currently, our knowledge of the determinants of severe COVID-19 is primarily observational. Here, I review emerging evidence to argue that monocytes, a circulating innate immune cell, are principal players in cytokine storm and associated pathologies in COVID-19. I also describe changes in monocyte function and phenotype that are characteristic of both aging and severe COVID-19, which suggests a potential mechanism underlying increased morbidity and mortality due to SARS-CoV-2 infection in older adults. The innate immune system is therefore a potentially important target for therapeutic treatment of COVID-19, but experimental studies are needed, and SARS-CoV-2 presents unique challenges for pre-clinical and mechanistic studies in vivo. The immediate establishment of colonies of SARS-CoV-2-susceptible animal models for aging studies, as well as strong collaborative efforts in the geroscience community, will be required in order to develop the therapies needed to combat severe COVID-19 in older adult populations.

Title: COVID-19 and the Heart. Content: Infection with the novel coronavirus, SARS-CoV-2, produces a clinical syndrome known as COVID-19. When severe, COVID-19 is a systemic illness characterized by hyperinflammation, cytokine storm and elevations of cardiac injury biomarkers. Here we review what is known about the pathophysiology of COVID-19, its cardiovascular manifestations, and emerging therapeutic prospects. In this rapidly moving field, this review was comprehensive as of April 3, 2020.

Title: Targeting the catecholamine-cytokine axis to prevent SARS-CoV-2 cytokine storm syndrome Content: The mortality of Coronavirus disease 2019 (COVID-19) appears to be driven by acute respiratory distress syndrome (ARDS) and a dysregulated immune response to SARS-CoV-2. Emerging evidence suggests that a subset of COVID-19 is characterized by the development of a cytokine storm syndrome (CSS), and interleukin (IL)-6 levels are predictors of COVID-19 severity and in-hospital mortality. Targeting hyper-inflammation in COVID-19 may be critical for reducing mortality. Catecholamines enhance inflammatory injury by augmenting the production of IL-6 and other cytokines through a self-amplifying feed-forward loop in immune cells that requires alpha-1 adrenergic receptor (α1-AR) signaling. Prophylactic inhibition of catecholamine synthesis with the α1-AR antagonist prazosin reduced catecholamines and cytokine responses in mice, and resulted in markedly increased survival following various hyper-inflammatory stimuli. These findings offer a rationale for studying α1-AR antagonists in the prophylaxis of patients with COVID-19-CSS and ARDS. As high infection rates threaten to overwhelm hospital capacity during this pandemic, preventative approaches that ameliorate COVID-19 severity and reduce excessive mortality are desperately needed. We hypothesize that treatment with prazosin of individuals who test positive for SARS-CoV-2 could reduce catecholamine surges, secondary cytokine dysregulation, and mortality. To investigate a potential role for α1-AR antagonists in preventing poor outcomes in ARDS, we conducted a retrospective analysis of hospitalized patients diagnosed with ARDS. Using data from the Truven Health MarketScan Research Database (2010-2017), we identified 13,125 men (age 45-64) with ARDS, of whom 655 patients (5.0%) were prescribed α1-AR antagonists in the previous year. Applying logistic regression models, we found that patients with prior use of α1-AR antagonists had lower odds of invasive mechanical ventilation compared to non-users (adjusted OR=0.75, 95% CI 0.59-0.95, p=0.019). Perhaps more importantly, those patients had a ~36% lower incidence of both being ventilated and dying in the hospital (adjusted OR=0.59, 95% CI 0.34-0.95, p=0.042). By contrast, prior use of beta-adrenergic receptor (β-AR) antagonists was not correlated with either outcome. We extended these analyses to patients admitted with pneumonia. Of 108,956 subjects in this cohort, 5,498 patients (5.0%) were taking α1-AR antagonist. Similar to ARDS, patients with pneumonia on α1-AR antagonists (but no β-AR antagonists) had a lower odds of mechanical ventilation (adjusted OR=0.83, 95% CI 0.75-0.92, p<0.001) and of both being ventilated and dying in the hospital (adjusted OR=0.77, 95% CI 0.62-0.94, p=0.014) compared to non-users. Mirroring findings from pre-clinical models, these data support a clinical rationale to study α1-AR antagonists in the prevention of severe complications of pneumonia, ARDS, and COVID-19. Prospective, randomized clinical trials of alpha-1 receptor antagonists (e.g. prazosin) administered prior to the onset of severe symptoms are needed to assess their efficacy in preventing CSS and reducing mortality in COVID-19.

Title: The novel immunomodulatory biologic LMWF5A for pharmacological attenuation of the “cytokine storm” in COVID-19 patients: a hypothesis Content: BACKGROUND: A common complication of viral pulmonary infections, such as in the ongoing COVID-19 pandemic, is a phenomenon described as a “cytokine storm”. While poorly defined, this hyperinflammatory response results in diffuse alveolar damage. The low molecular weight fraction of commercial human serum albumin (LMWF5A), a novel biologic in development for osteoarthritis, demonstrates beneficial in vitro immunomodulatory effects complimentary to addressing inflammation, thus, we hypothesize that LMWF5A could improve the clinical outcomes of COVID-19 by attenuating hyperinflammation and the potential development of a cytokine storm. PRESENTATION OF THE HYPOTHESIS: A variety of human in vitro immune models indicate that LMWF5A reduces the production of pro-inflammatory cytokines implicated in cytokine storm associated with COVID-19. Furthermore, evidence suggests LMWF5A also promotes the production of mediators required for resolving inflammation and enhances the barrier function of endothelial cultures. TESTING THE HYPOTHESIS: A randomized controlled trial, to evaluate the safety and efficacy of nebulized LMWF5A in adults with Acute Respiratory Distress Syndrome (ARDS) secondary to COVID-19 infection, was developed and is currently under review by the Food and Drug Administration. IMPLICATIONS OF HYPOTHESIS: If successful, this therapy may attenuate the cytokine storm observed in these patients and potentially reduce mortality, increase ventilation free days, improve oxygenation parameters and consequently lessen the burden on patients and the intensive care unit. CONCLUSIONS: In conclusion, in vitro findings suggest that the immunomodulatory effects of LMWF5A make it a viable candidate for treating cytokine storm and restoring homeostasis to the immune response in COVID-19.

Title: Posterior Reversible Encephalopathy Syndrome: A Manifestation of COVID-19 Cytokine Storm Content: Neuroimaging manifestations of COVID-19 are being reported with increasing frequency with recent reports of associated atypical leukoencephalopathies. We add to this literature by describing a COVID-19 + patient who demonstrated imaging findings typical for posterior reversible encephalopathy syndrome (PRES). The inflammatory syndrome associated with novel corona virus infection has shown markedly increased levels of cytokines and inflammatory markers. This has also been described in a proposed mechanism for PRES, where elevated inflammatory markers result in endothelial injury causing interstitial fluid extravasation typical of PRES. We expect that other cases of PRES will be observed in this population given the scope of the Covid-19 pandemic.

Title: 2019 Novel Coronavirus Pandemic: What Do We Know? Content: The pandemic caused by SARS-COV2 Virus/COVID-19, which was initially reported in China in December 2019, has become a major global health concern COVID-19 can manifest with cytokine storm - an exaggerated systemic inflammatory phenomenon due to over-production of proinflammatory cytokines by immune cells that results in diffuse inflammatory lung disease and acute respiratory distress syndrome It may be complicated by septic shock and subsequent multi-organ failure Based on the most recently published evidence, this article will review and discuss comprehensive information on its clinical manifestations, laboratory tests, potential therapeutics, and prevention guidelines

Title: 2019 Novel Coronavirus Pandemic: What Do We Know? Content: The pandemic caused by SARS-COV2 Virus/COVID-19, which was initially reported in China in December 2019, has become a major global health concern. COVID-19 can manifest with cytokine storm - an exaggerated systemic inflammatory phenomenon due to over-production of proinflammatory cytokines by immune cells that results in diffuse inflammatory lung disease and acute respiratory distress syndrome. It may be complicated by septic shock and subsequent multi-organ failure. Based on the most recently published evidence, this article will review and discuss comprehensive information on its clinical manifestations, laboratory tests, potential therapeutics, and prevention guidelines.

Title: Commentary: Phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19 Content: The most severe presentation of COVID-19 is characterized by a hyperinflammatory state attributed to the massive pro-inflammatory cytokine release, called “cytokine storm”. Several specific anti-inflammatory/immunosuppressive agents are being evaluated by ongoing clinical trials; however, there is currently insufficient evidence for their efficacy and safety in COVID-19 treatment. Given the role of phosphodiesterase 4 (PDE) 4 and cyclic adenosine monophosphate in the inflammatory response, we hypothesize that selective PDE4 inhibition may attenuate the cytokine storm in COVID-19, through the upstream inhibition of pro-inflammatory molecules, particularly TNF-α, and the regulation of the pro-inflammatory/anti-inflammatory balance. Conversely, other anti-cytokine agents lead to the downstream inhibition of specific targets, such as IL-1, IL-6 or TNF-α, and may not be efficient in blocking the cytokine storm, once it has been triggered. Due to their mechanism of action targeting an early stage of the inflammatory response and ameliorating lung inflammation, we believe that selective PDE4 inhibitors may represent a promising treatment option for the early phase of COVID-19 pneumonia before the cytokine storm and severe multiorgan dysfunction take place. Furthermore, PDE4 inhibitors present several advantages including an excellent safety profile; the oral route of administration; the convenient dosing; and beneficial metabolic properties. Interestingly, obesity and diabetes mellitus type 2 have been reported to be risk factors for the severity of COVID-19. Therefore, randomized clinical trials of PDE4 inhibitors are necessary to explore their potential therapeutic effect as an adjunct to supportive measures and other therapeutic regiments.

Title: Commentary: Phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19 Content: The most severe presentation of COVID-19 is characterized by a hyperinflammatory state attributed to the massive pro-inflammatory cytokine release, called "cytokine storm". Several specific anti-inflammatory/immunosuppressive agents are being evaluated by ongoing clinical trials; however, there is currently insufficient evidence for their efficacy and safety in COVID-19 treatment. Given the role of phosphodiesterase 4 (PDE) 4 and cyclic adenosine monophosphate in the inflammatory response, we hypothesize that selective PDE4 inhibition may attenuate the cytokine storm in COVID-19, through the upstream inhibition of pro-inflammatory molecules, particularly TNF-α, and the regulation of the pro-inflammatory/anti-inflammatory balance. Conversely, other anti-cytokine agents lead to the downstream inhibition of specific targets, such as IL-1, IL-6 or TNF-α, and may not be efficient in blocking the cytokine storm, once it has been triggered. Due to their mechanism of action targeting an early stage of the inflammatory response and ameliorating lung inflammation, we believe that selective PDE4 inhibitors may represent a promising treatment option for the early phase of COVID-19 pneumonia before the cytokine storm and severe multiorgan dysfunction take place. Furthermore, PDE4 inhibitors present several advantages including an excellent safety profile; the oral route of administration; the convenient dosing; and beneficial metabolic properties. Interestingly, obesity and diabetes mellitus type 2 have been reported to be risk factors for the severity of COVID-19. Therefore, randomized clinical trials of PDE4 inhibitors are necessary to explore their potential therapeutic effect as an adjunct to supportive measures and other therapeutic regiments.

Title: Adjunct immunotherapies for the management of severely ill COVID-19 patients Content: Abstract Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has infected millions with more than 181,000 fatal cases as of 22nd April 2020. Currently, there are no specific COVID-19 therapies. Most patients depend on mechanical ventilation. Current COVID-19 data clearly highlight that cytokine storm and activated immune cell migration to the lungs characterize the early immune response to COVID-19 that causes severe lung damage and development of acute respiratory distress syndrome. In view of uncertainty associated with immunosuppressive treatments such as corticosteroids and their possible secondary effects, including risks of secondary infections, we suggest immunotherapies as an adjunct therapy in severe COVID-19 cases. Such immunotherapies based on inflammatory cytokine neutralization, immunomodulation and passive viral neutralization, not only reduce inflammation, inflammation-associated lung damage, or viral load, but could also prevent intensive care unit hospitalization and dependency on mechanical ventilation both of which are limited resources.

Title: Adjunct Immunotherapies for the Management of Severely Ill COVID-19 Patients Content: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has infected millions, with more than 275,000 fatal cases as of May 8, 2020. Currently, there are no specific COVID-19 therapies. Most patients depend on mechanical ventilation. Current COVID-19 data clearly highlight that cytokine storm and activated immune cell migration to the lungs characterize the early immune response to COVID-19 that causes severe lung damage and development of acute respiratory distress syndrome. In view of uncertainty associated with immunosuppressive treatments, such as corticosteroids and their possible secondary effects, including risks of secondary infections, we suggest immunotherapies as an adjunct therapy in severe COVID-19 cases. Such immunotherapies based on inflammatory cytokine neutralization, immunomodulation, and passive viral neutralization not only reduce inflammation, inflammation-associated lung damage, or viral load but could also prevent intensive care unit hospitalization and dependency on mechanical ventilation, both of which are limited resources.

Title: COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons Content: The outbreak of the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) responsible for coronavirus disease 2019 (COVID-19) has developed into an unprecedented global pandemic. Clinical investigations in patients with COVID-19 has shown a strong upregulation of cytokine and interferon production in SARS-CoV2- induced pneumonia, with an associated cytokine storm syndrome. Thus, the identification of existing approved therapies with proven safety profiles to treat hyperinflammation is a critical unmet need in order to reduce COVI-19 associated mortality. To date, no specific therapeutic drugs or vaccines are available to treat COVID-19 patients. This review evaluates several options that have been proposed to control SARS-CoV2 hyperinflammation and cytokine storm, eincluding antiviral drugs, vaccines, small-molecules, monoclonal antibodies, oligonucleotides, peptides, and interferons (IFNs).

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: Covid-19 nephropathy: What could pathologist say? Content: Implication for health policy/practice/research/medical education: The pathogenetic mechanism of renal involvement in coronavirus disease 19 (COVID-19) is still unclear. It is supposed to result from a combination of several contributing factors, such as state of dehydration, leading to pre-renal failure with acute tubular necrosis, toxic tubular damage, induced by cytokine storm or rhabdomyolysis, cytopathic action induced by the virus that invades ACE2- expressing kidney cells and drug-induced nephrotoxicity.

Title: Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial Content: INTRODUCTION: The rapid worldwide spread of COVID-19 has caused a global health crisis. To date, symptomatic supportive care has been the most common treatment. It has been reported that the mechanism of COVID-19 is related to cytokine storms and subsequent immunogenic damage, especially damage to the endothelium and alveolar membrane. Vitamin C (VC), also known as L-ascorbic acid, has been shown to have antimicrobial and immunomodulatory properties. A high dose of intravenous VC (HIVC) was proven to block several key components of cytokine storms, and HIVC showed safety and varying degrees of efficacy in clinical trials conducted on patients with bacterial-induced sepsis and acute respiratory distress syndrome (ARDS). Therefore, we hypothesise that HIVC could be added to the treatment of ARDS and multiorgan dysfunction related to COVID-19. METHODS AND ANALYSIS: The investigators designed a multicentre prospective randomised placebo-controlled trial that is planned to recruit 308 adults diagnosed with COVID-19 and transferred into the intensive care unit. Participants will randomly receive HIVC diluted in sterile water or placebo for 7 days once enrolled. Patients with a history of VC allergy, end-stage pulmonary disease, advanced malignancy or glucose-6-phosphate dehydrogenase deficiency will be excluded. The primary outcome is ventilation-free days within 28 observational days. This is one of the first clinical trials applying HIVC to treat COVID-19, and it will provide credible efficacy and safety data. We predict that HIVC could suppress cytokine storms caused by COVID-19, help improve pulmonary function and reduce the risk of ARDS of COVID-19. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (identifiers: Clinical Ethical Approval No. 2020001). Findings of the trial will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER: NCT04264533.

Title: JAK1 inhibition blocks lethal sterile immune responses: implications for COVID-19 therapy Content: Cytokine storms are drivers of pathology and mortality in myriad viral infections affecting the human population. In SARS-CoV-2-infected patients, the strength of the cytokine storm has been associated with increased risk of acute respiratory distress syndrome, myocardial damage, and death. However, the therapeutic value of attenuating the cytokine storm in COVID-19 remains to be defined. Here, we report results obtained using a novel mouse model of lethal sterile anti-viral immune responses. Using a mouse model of Down syndrome (DS) with a segmental duplication of a genomic region encoding four of the six interferon receptor genes (Ifnrs), we demonstrate that these animals overexpress Ifnrs and are hypersensitive to IFN stimulation. When challenged with viral mimetics that activate Toll-like receptor signaling and IFN anti-viral responses, these animals overproduce key cytokines, show exacerbated liver pathology, rapidly lose weight, and die. Importantly, the lethal immune hypersensitivity, accompanying cytokine storm, and liver hyperinflammation are blocked by treatment with a JAK1-specific inhibitor. Therefore, these results point to JAK1 inhibition as a potential strategy for attenuating the cytokine storm and consequent organ failure during overdrive immune responses. Additionally, these results indicate that people with DS, who carry an extra copy of the IFNR gene cluster encoded on chromosome 21, should be considered at high risk during the COVID-19 pandemic. One Sentence Summary Inhibition of the JAK1 kinase prevents pathology and mortality caused by a rampant innate immune response in mice.

Title: Role of poly (ADP) ribose polymerase-1 inhibition by nicotinamide as a possible additive treatment to modulate host immune response and prevention of cytokine storm in COVID-19 Content: COVID-19 is rapidly spreading contagious disease spreading across the world. Patients at risk are elderly people and those with comorbidity. Early studies done on Chinese patients who suggest cytokine storm to be responsible for lung injury. We need to understand the mechanism of modulating such robust response of immunity and resultant cytokine storm. We suggest nicotinamide, a potential poly ADP ribose polymerase (PARP) inhibitor, as a supportive treatment for the prevention of cytokine storm from injuring the lung parenchyma. Nicotinamide supplementation albeit at high dose may modulate outcome in COVID-19. Nicotinamide was used previously to reduce ventilator-induced lung injury and lung injury due to hypoxia. Nicotinamide congeners are used to treat chronic lung disease like tuberculosis. Certainly, nicotinamide is effective pharmacotherapy in lung injury – whether acute or chronic. Other measures used in treating COVID-19 are focusing on targeting interleukin-6 – a cytokine responsible for mayhem, while few are targeting granulocyte-macrophage colony- stimulating factor. We suggest targeting PARP in addition to other measures to block cytokines. By inhibiting PARP course of COVID-19 may be altered. Understanding the pathophysiology of acute lung injury is crucial. PARP plays a pivotal role on cytokine release in response to any lung injury ranging from viral infection to hypoxia. Various antiviral defenses and immune response need to be studied in detail.

Title: Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use Content: COVID-19 has affected the United States leading to a national emergency with health care and economic impact, propelling the country into a recession with disrupted lifestyles not seen in recent history. COVID-19 is a serious illness leading to multiple deaths in various countries including the United States. Several million Americans satisfy the Center for Disease Control and Prevention (CDC) criteria for being high risk. Unfortunately, the available supply of medical beds and equipment for mechanical ventilation are much less than is projected to be needed. The World Health Organization (WHO) and multiple agencies led by the CDC in the United States have attempted to organize intensive outbreak investigation programs utilizing appropriate preventive measures, evaluation, and treatment. The clinical spectrum of COVID-19 varies from asymptomatic forms to conditions encompassing multiorgan and systemic manifestations in terms of septic shock, and multiple organ dysfunction (MOD) syndromes. The presently approved treatments are supportive but not curative for the disease. There are multiple treatments being studied. These include vaccines, medications Remdesivir and hydroxychloroquine and potentially combination therapy. Finally, expanded umbilical cord mesenchymal stem cells or (UC-MSCs) may have a role and are being studied. The cure of COVID-19 is essentially dependent on the patients' own immune system. When the immune system is over activated in an attempt to kill the virus, this can lead to the production of a large number of inflammatory factors, resulting in severe cytokine storm. The cytokine storm may induce organ damage followed by the edema, dysfunction of air exchange, acute respiratory distress syndrome (ARDS), acute cardiac injury, and secondary infection, which may lead to death. Thus, at this point, the avoidance of the cytokine storm may be the key for the treatment of HCOV-19 infected patients.In China, where there was limited availability of effective modalities to manage COVID-19 several patients were treated with expanded UC-MSCs. Additionally, the Italian College of Anesthesia, Analgesia, Resuscitation and Intensive Care have reported guidelines to treat coronavirus patients with stem cells in the hope of decreasing the number of patients going to the ICU, and, also relatively quickly getting them out of ICU. In this manuscript, we describe the urgent need for various solutions, pathogenesis of coronavirus and the clinical evidence for treatment of COVID-19 with stem cells. The limited but emerging evidence regarding UC MSC in managing COVID-19 suggests that it might be considered for compassionate use in critically ill patients to reduce morbidity and mortality in the United States. The administration and Coronavirus Task Force might wish to approach the potential of expanded UC-MSCs as an evolutionary therapeutic strategy in managing COVID-19 illness with a 3-pronged approach: If proven safe and effective on a specific and limited basis 1. Minimize regulatory burden by all agencies so that critically ill COVID-19 patients will have access regardless of their financial circumstance.2. Institute appropriate safeguards to avoid negative consequences from unscrupulous actors.3. With proper informed consent from patients or proxy when necessary, and subject to accumulation of data in that cohort, allow the procedure to be initiated in critically ill patients who are not responding to conventional therapies.KEY WORDS: Coronavirus, COVID-19, cytokine storm, multiorgan failure, expanded umbilical cord mesenchymal stem cells.

Title: Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use. Content: COVID-19 has affected the United States leading to a national emergency with health care and economic impact, propelling the country into a recession with disrupted lifestyles not seen in recent history. COVID-19 is a serious illness leading to multiple deaths in various countries including the United States. Several million Americans satisfy the Center for Disease Control and Prevention (CDC) criteria for being high risk. Unfortunately, the available supply of medical beds and equipment for mechanical ventilation are much less than is projected to be needed. The World Health Organization (WHO) and multiple agencies led by the CDC in the United States have attempted to organize intensive outbreak investigation programs utilizing appropriate preventive measures, evaluation, and treatment. The clinical spectrum of COVID-19 varies from asymptomatic forms to conditions encompassing multiorgan and systemic manifestations in terms of septic shock, and multiple organ dysfunction (MOD) syndromes. The presently approved treatments are supportive but not curative for the disease. There are multiple treatments being studied. These include vaccines, medications Remdesivir and hydroxychloroquine and potentially combination therapy. Finally, expanded umbilical cord mesenchymal stem cells or (UC-MSCs) may have a role and are being studied. The cure of COVID-19 is essentially dependent on the patients' own immune system. When the immune system is over activated in an attempt to kill the virus, this can lead to the production of a large number of inflammatory factors, resulting in severe cytokine storm. The cytokine storm may induce organ damage followed by the edema, dysfunction of air exchange, acute respiratory distress syndrome (ARDS), acute cardiac injury, and secondary infection, which may lead to death. Thus, at this point, the avoidance of the cytokine storm may be the key for the treatment of HCOV-19 infected patients.In China, where there was limited availability of effective modalities to manage COVID-19 several patients were treated with expanded UC-MSCs. Additionally, the Italian College of Anesthesia, Analgesia, Resuscitation and Intensive Care have reported guidelines to treat coronavirus patients with stem cells in the hope of decreasing the number of patients going to the ICU, and, also relatively quickly getting them out of ICU. In this manuscript, we describe the urgent need for various solutions, pathogenesis of coronavirus and the clinical evidence for treatment of COVID-19 with stem cells. The limited but emerging evidence regarding UC MSC in managing COVID-19 suggests that it might be considered for compassionate use in critically ill patients to reduce morbidity and mortality in the United States. The administration and Coronavirus Task Force might wish to approach the potential of expanded UC-MSCs as an evolutionary therapeutic strategy in managing COVID-19 illness with a 3-pronged approach: If proven safe and effective on a specific and limited basis…1. Minimize regulatory burden by all agencies so that critically ill COVID-19 patients will have access regardless of their financial circumstance.2. Institute appropriate safeguards to avoid negative consequences from unscrupulous actors.3. With proper informed consent from patients or proxy when necessary, and subject to accumulation of data in that cohort, allow the procedure to be initiated in critically ill patients who are not responding to conventional therapies.KEY WORDS: Coronavirus, COVID-19, cytokine storm, multiorgan failure, expanded umbilical cord mesenchymal stem cells.

Title: Successful recovery of severe COVID-19 with cytokine storm treating with extracorporeal blood purification Content: COVID-19 associated cytokine storm could induce ARDS rapidly and the patients would require the support of mechanic ventilation. However, the prognosis was not that optimistic. The outcome might be changed if the intervention of EBP was performed timely. We present a case of severe SARS-CoV-2 infection who recovered from cytokine storm.

Title: Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes Content: A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.

Title: Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes Content: A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a “Cytokine Storm Syndrome” (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.

Title: Targeting lymphocyte Kv1.3-channels to suppress cytokine storm in severe COVID-19: Can it be a novel therapeutic strategy? Content: In the midst of a pandemic, finding effective treatments for coronavirus disease 2019 (COVID-19) is the urgent issue. In "chronic inflammatory diseases", the overexpression of delayed rectifier K+-channels (Kv1.3) in leukocytes is responsible for the overactivation of cellular immunity and the subsequent cytokine storm. In our previous basic studies, drugs including chloroquine and azithromycin strongly suppressed the channel activity and pro-inflammatory cytokine production from lymphocytes. These findings suggest a novel pharmacological mechanism by which chloroquine, with or without azithromycin, is effective for severe cases of COVID-19, in which the overactivation of cellular immunity and the subsequent cytokine storm are responsible for the pathogenesis.

Title: Cytokine Storm in COVID-19 patients transforms to a Cytokine Super Cyclone in patients with risk factors Content: The seventh human coronavirus SARS-CoV2 belongs to the cluster of extremely pathogenic coronaviruses like SARS-CoV and MERS-CoV, which are established to cause lower respiratory tract infection. The viral infection can be fatal as the disease advances to pneumonia followed by acute respiratory distress syndrome (ARDS). Increasingly higher cytokine concentration on account of over-stimulated immune response against the virus, or the ‘cytokine storm’, is the reason behind the manifestation of lethal clinical symptoms. In this article, we discuss the immune pathogenesis of cytokine storm and its relation with SARS-CoV2/COVID-19 risk factors. People with underlying risk factors are more susceptible to fatal complications of COVID-19 infection leading to poor clinical outcome. The increased pro-inflammatory immune status in patients with risk factors (diabetes, hypertension, cardiovascular disease, COPD) exacerbates the Cytokine-storm of COVID-19 to a Cytokine Super Cyclone. We also overviewed antiviral immune response provided by BCG vaccine involving the IL-1β, IL-6 and TNF-α secretion via ‘trained monocytes’, which confers early protection against SARS-CoV2.

Title: Lymphopenia in COVID-19: Therapeutic opportunities Content: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is uncontrollably spread all over the world. The host immune responses strongly try to confront it with all the potential cells and cytokines. With chronically condition of SARS-CoV-2, natural killer cells and T cells become exhausted and decreasing their count leads to lymphopenia. Inability to eradicate the infected organ makes hyperinitiation of the immune system, which releases the excessive inflammatory cytokines to compensate the exhausted one as well as the low lymphocytes counts; it consequently leads to the cytokine storm syndrome. These mechanisms and the potential therapeutic targeting are discussed in this paper.

Title: Lymphopenia in COVID‐19: Therapeutic opportunities Content: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is uncontrollably spread all over the world. The host immune responses strongly try to confront it with all the potential cells and cytokines. With chronically condition of SARS‐CoV‐2, natural killer cells and T cells become exhausted and decreasing their count leads to lymphopenia. Inability to eradicate the infected organ makes hyperinitiation of the immune system, which releases the excessive inflammatory cytokines to compensate the exhausted one as well as the low lymphocytes counts; it consequently leads to the cytokine storm syndrome. These mechanisms and the potential therapeutic targeting are discussed in this paper.

Title: Cytokine storm in COVID‐19 and parthenolide: preclinical evidence Content: A group of patients with pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) were reported from China in December 2019. Although several antiviral drugs are widely tested, none of them has been approved as specific antiviral therapy for coronavirus disease 2019 (COVID‐19). Accumulating evidence established a hyperinflammatory states or cytokine storm in COVID‐19. Among these cytokines, IL‐6 plays a key role in cytokine storm and can predict the adverse clinical outcomes and fatality in these patients. Based on the evidence of the significant role of IL‐6 in cytokine storm, diabetes mellitus and cardiovascular diseases as principal comorbidities, it seems that anti‐cytokine therapy may be useful in patients with severe COVID‐19 to reduce mortality. Recent studies demonstrated that herbal‐derived natural products had immunosuppressive and anti‐inflammatory properties and exhibited exceptional act on mediators of inflammation. Parthenolide is the principal sesquiterpene lactones and the main biologically active constituent Tanacetum parthenium (commonly known as feverfew) which has could significantly reduce IL‐1, IL‐2, IL‐6, IL‐8, and TNF‐α production pathways established in several human cell line models in vitro and in vivo studies. Therefore, parthenolide may be one of the herbal candidates for clinical evaluation. This article is protected by copyright. All rights reserved.

Title: Cytokine storm in COVID-19 and parthenolide: Preclinical evidence Content: A group of patients with pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were reported from China in December 2019. Although several antiviral drugs are widely tested, none of them has been approved as specific antiviral therapy for coronavirus disease 2019 (COVID-19). Accumulating evidence established a hyperinflammatory states or cytokine storm in COVID-19. Among these cytokines, IL-6 plays a key role in cytokine storm and can predict the adverse clinical outcomes and fatality in these patients. Based on the evidence of the significant role of IL-6 in cytokine storm, diabetes mellitus, and cardiovascular diseases as principal comorbidities, it seems that anti-cytokine therapy may be useful in patients with severe COVID-19 to reduce mortality. Recent studies demonstrated that herbal-derived natural products had immunosuppressive and anti-inflammatory properties and exhibited exceptional act on mediators of inflammation. Parthenolide is the principal sesquiterpene lactones and the main biologically active constituent Tanacetum parthenium (commonly known as feverfew) which has could significantly reduce IL-1, IL-2, IL-6, IL-8, and TNF-α production pathways established in several human cell line models in vitro and in vivo studies. Therefore, parthenolide may be one of the herbal candidates for clinical evaluation.

Title: Cytokine storm intervention in the early stages of COVID-19 pneumonia Content: Abstract Clinical intervention in patients with corona virus disease 2019 (COVID-19) has demonstrated a strong upregulation of cytokine production in patients who are critically ill with SARS-CoV2-induced pneumonia. In a retrospective study of 41 patients with COVID-19, most patients with SARS-CoV-2 infection developed mild symptoms, whereas some patients later developed aggravated disease symptoms, and eventually passed away because of multiple organ dysfunction syndrome (MODS), as a consequence of a severe cytokine storm. Guidelines for the diagnosis and treatment of SARS-CoV-2 infected pneumonia were first published January 30th, 2020; these guidelines recommended for the first time that cytokine monitoring should be applied in severely ill patients to reduce pneumonia related mortality. The cytokine storm observed in COVID-19 illness is also an important component of mortality in other viral diseases, including SARS, MERS and influenza. In view of the severe morbidity and mortality of COVID-19 pneumonia, we review the current understanding of treatment of human coronavirus infections from the perspective of a dysregulated cytokine and immune response.

Title: Cytokine storm intervention in the early stages of COVID-19 pneumonia Content: Clinical intervention in patients with corona virus disease 2019 (COVID-19) has demonstrated a strong upregulation of cytokine production in patients who are critically ill with SARS-CoV2-induced pneumonia. In a retrospective study of 41 patients with COVID-19, most patients with SARS-CoV-2 infection developed mild symptoms, whereas some patients later developed aggravated disease symptoms, and eventually passed away because of multiple organ dysfunction syndrome (MODS), as a consequence of a severe cytokine storm. Guidelines for the diagnosis and treatment of SARS-CoV-2 infected pneumonia were first published January 30th, 2020; these guidelines recommended for the first time that cytokine monitoring should be applied in severely ill patients to reduce pneumonia related mortality. The cytokine storm observed in COVID-19 illness is also an important component of mortality in other viral diseases, including SARS, MERS and influenza. In view of the severe morbidity and mortality of COVID-19 pneumonia, we review the current understanding of treatment of human coronavirus infections from the perspective of a dysregulated cytokine and immune response.

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: Preventing cytokine storm syndrome in COVID-19 using α-1 adrenergic receptor antagonists. Content: Medications that target catecholamine-associated inflammation may prevent cytokine storm syndrome associated with COVID-19 and other diseases.

Title: Alpha-1 adrenergic receptor antagonists for preventing acute respiratory distress syndrome and death from cytokine storm syndrome Content: In severe viral pneumonias, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by a hyperinflammatory reaction ('cytokine storm syndrome') that leads to acute respiratory distress syndrome and death, despite maximal supportive care. Preventing hyperinflammation is key to avoiding these outcomes. We previously demonstrated that alpha-1 adrenergic receptor antagonists ($\alpha$-blockers) can prevent cytokine storm syndrome and death in mice. Here, we conduct a retrospective analysis of patients with acute respiratory distress or pneumonia (n = 13,125 and n = 108,956, respectively) from all causes; patients who were incidentally taking $\alpha$-blockers had a reduced risk of requiring ventilation (by 35% and 16%, respectively), and a reduced risk of being ventilated and dying (by 56% and 20%, respectively), compared to non-users. Beta-adrenergic receptor antagonists had no significant effects. These results highlight the urgent need for prospective trials testing whether prophylactic $\alpha$-blockers improve outcomes in diseases with a prominent hyperinflammatory component such as COVID-19.

Title: Alpha-1 adrenergic receptor antagonists for preventing acute respiratory distress syndrome and death from cytokine storm syndrome. Content: In severe viral pneumonias, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by a hyperinflammatory reaction ('cytokine storm syndrome') that leads to acute respiratory distress syndrome and death, despite maximal supportive care. Preventing hyperinflammation is key to avoiding these outcomes. We previously demonstrated that alpha-1 adrenergic receptor antagonists ($\alpha$-blockers) can prevent cytokine storm syndrome and death in mice. Here, we conduct a retrospective analysis of patients with acute respiratory distress or pneumonia (n = 13,125 and n = 108,956, respectively) from all causes; patients who were incidentally taking $\alpha$-blockers had a reduced risk of requiring ventilation (by 35% and 16%, respectively), and a reduced risk of being ventilated and dying (by 56% and 20%, respectively), compared to non-users. Beta-adrenergic receptor antagonists had no significant effects. These results highlight the urgent need for prospective trials testing whether prophylactic $\alpha$-blockers improve outcomes in diseases with a prominent hyperinflammatory component such as COVID-19.

Title: Role of oxidized LDL-induced "trained macrophages" in the pathogenesis of COVID-19 and benefits of pioglitazone: A hypothesis Content: BACKGROUND AND AIMS: Older adults and people who have cardiovascular disorders (their common pathogenetic mechanism is progressive atherosclerosis) are at higher risk for severe illness from COVID-19 (coronavirus disease 2019). Their common pathogenetic mechanism is progressive atherosclerosis in which oxLDL (oxidized LDL) plays major role. Receptor-mediated uptake of oxLDL by the monocyte-derived macrophages activates the long-term epigenetic reprogramming of innate immunity, which is termed "trained immunity." The aim of this work is to investigate the mechanisms and treatment possibilities that can control the activities of these specific macrophages. METHODS: Search in Medline and PubMed relevant articles on the trained immunity and cytokine storm of COVID-19. RESULTS AND CONCLUSIONS: When oxLDL-trained macrophages encounter SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in the lung, it causes unregulated cytokine secretion, leading to the alveolar damage. Therefore, blocking macrophage training by pioglitazone, a thiazolidinedione, could control the hyperactivation that the virus would trigger.

Title: Role of oxidized LDL-induced “trained macrophages” in the pathogenesis of COVID-19 and benefits of pioglitazone: A hypothesis Content: BACKGROUND AND AIMS: Older adults and people who have cardiovascular disorders (their common pathogenetic mechanism is progressive atherosclerosis) are at higher risk for severe illness from COVID-19 (coronavirus disease 2019). Their common pathogenetic mechanism is progressive atherosclerosis in which oxLDL (oxidized LDL) plays major role. Receptor-mediated uptake of oxLDL by the monocyte-derived macrophages activates the long-term epigenetic reprogramming of innate immunity, which is termed “trained immunity.” The aim of this work is to investigate the mechanisms and treatment possibilities that can control the activities of these specific macrophages. METHODS: Search in Medline and PubMed relevant articles on the trained immunity and cytokine storm of COVID-19. CONCLUSIONS: When oxLDL-trained macrophages encounter SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in the lung, it causes unregulated cytokine secretion, leading to the alveolar damage. Therefore, blocking macrophage training by pioglitazone, a thiazolidinedione, could control the hyperactivation that the virus would trigger.

Title: COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome? Content: The severe form of COVID-19 share several clinical and laboratory features with four entities gathered under the term "hyperferritinemic syndromes" and including macrophage activation syndrome (MAS), adult-onset Still's disease (AOSD), catastrophic anti-phospholipid syndrome (CAPS) and septic shock. COVID-19 systemic inflammatory reaction and "hyperferritinemic syndromes" are all characterized by high serum ferritin and a life-threatening hyper-inflammation sustained by a cytokines storm which eventually leads to multi-organ failure. In this review, we analyze the possible epidemiological and molecular mechanisms responsible for hyper-inflammation in patients with severe COVID-19 and we underline the similarities between this condition and "hyperferritinemic syndromes" which would allow considering severe COVID-19 as a fifth member of this spectrum of inflammatory conditions.

Title: Dipeptidyl peptidase-4 (DPP4) inhibition in COVID-19 Content: AIMS: SARS-CoV-2 causes severe respiratory syndrome (COVID-19) with high mortality due to a direct cytotoxic viral effect and a severe systemic inflammation. We are herein discussing a possible novel therapeutic tool for COVID-19. METHODS: Virus binds to the cell surface receptor ACE2; indeed, recent evidences suggested that SARS-CoV-2 may be using as co-receptor, when entering the cells, the same one used by MERS-Co-V, namely the DPP4/CD26 receptor. The aforementioned observation underlined that mechanism of cell entry is supposedly similar among different coronavirus, that the co-expression of ACE2 and DPP4/CD26 could identify those cells targeted by different human coronaviruses and that clinical complications may be similar. RESULTS: The DPP4 family/system was implicated in various physiological processes and diseases of the immune system, and DPP4/CD26 is variously expressed on epithelia and endothelia of the systemic vasculature, lung, kidney, small intestine and heart. In particular, DPP4 distribution in the human respiratory tract may facilitate the entrance of the virus into the airway tract itself and could contribute to the development of cytokine storm and immunopathology in causing fatal COVID-19 pneumonia. CONCLUSIONS: The use of DPP4 inhibitors, such as gliptins, in patients with COVID-19 with, or even without, type 2 diabetes, may offer a simple way to reduce the virus entry and replication into the airways and to hamper the sustained cytokine storm and inflammation within the lung in patients diagnosed with COVID-19 infection.

Title: Dipeptidyl peptidase-4 (DPP4) inhibition in COVID-19 Content: AIMS: SARS–CoV-2 causes severe respiratory syndrome (COVID-19) with high mortality due to a direct cytotoxic viral effect and a severe systemic inflammation. We are herein discussing a possible novel therapeutic tool for COVID-19. METHODS: Virus binds to the cell surface receptor ACE2; indeed, recent evidences suggested that SARS–CoV-2 may be using as co-receptor, when entering the cells, the same one used by MERS–Co-V, namely the DPP4/CD26 receptor. The aforementioned observation underlined that mechanism of cell entry is supposedly similar among different coronavirus, that the co-expression of ACE2 and DPP4/CD26 could identify those cells targeted by different human coronaviruses and that clinical complications may be similar. RESULTS: The DPP4 family/system was implicated in various physiological processes and diseases of the immune system, and DPP4/CD26 is variously expressed on epithelia and endothelia of the systemic vasculature, lung, kidney, small intestine and heart. In particular, DPP4 distribution in the human respiratory tract may facilitate the entrance of the virus into the airway tract itself and could contribute to the development of cytokine storm and immunopathology in causing fatal COVID-19 pneumonia. CONCLUSIONS: The use of DPP4 inhibitors, such as gliptins, in patients with COVID-19 with, or even without, type 2 diabetes, may offer a simple way to reduce the virus entry and replication into the airways and to hamper the sustained cytokine storm and inflammation within the lung in patients diagnosed with COVID-19 infection.

Title: COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome? Content: Abstract The severe form of COVID-19 share several clinical and laboratory features with four entities gathered under the term “hyperferritinemic syndrome” and including macrophage activation syndrome (MAS), adult-onset Still's disease (AOSD), catastrophic anti-phospholipid syndrome (CAPS) and septic shock. COVID-19 systemic inflammatory reaction and “hyperferritinemic syndromes” are all characterized by high serum ferritin and a life-threatening hyper-inflammation sustained by a cytokines storm which eventually leads to multi-organ failure. In this review, we analyze the possible epidemiological and molecular mechanisms responsible for hyper-inflammation in patients with severe COVID-19 and we underline the similarities between this condition and “hyperferritinemic syndromes” which would allow considering this entity as the fifth member of the spectrum of inflammatory conditions.

Title: Understanding the COVID‐19 coagulopathy spectrum Content: The SARS‐Cov‐2 (COVID‐19) pandemic has already claimed over 200,000 lives. Quite early on in this pandemic, it was recognised that the virus triggers the immune system leading to a cytokine storm in some severely ill patients [1]. This hyper‐responsiveness has been suggested to be the predominant aetiology for clinical deterioration and mortality in patients with this infection [2]. More recently, there have been several reports of increased thrombotic events in these patients [3‐6]. From a laboratory perspective, this hypercoagulability is reflected in the marked elevation of the fibrinolytic marker, D‐dimer, in almost all hospitalised COVID‐19 patients [7]. We must, therefore, ask ourselves what is the link between the extremes of the immune system, presenting as cytokine storm, and the extremes of coagulation, presenting as arterial and venous thromboembolism?

Title: Rapid Radiological Worsening and Cytokine Storm Syndrome in COVID-19 Pneumonia Content: BACKGROUND: In June 2020, a large randomised controlled clinical trial in the UK found that dexamethasone was effective in reducing the number of deaths in patients with severe coronavirus disease 2019 (COVID-19). CASE DESCRIPTION: We describe a patient with rapid worsening of COVID-19 pneumonia and its dramatic improvement under corticosteroids. DISCUSSION: Corticosteroids could be useful in patients with an inflammatory profile, considering that acute respiratory distress syndrome may be the consequence of cytokine storm syndrome. LEARNING POINTS: One of the main pathophysiological hypotheses for severe COVID-19 pneumonia is inappropriate immunological hyperactivation. Corticosteroid therapy may be useful in these patients.

Title: Cytokine Release Syndrome (CRS) and Nicotine in COVID-19 Patients: Trying to Calm the Storm Content: SARS-CoV-2 is a new coronavirus that has caused a worldwide pandemic. It causes severe acute respiratory syndrome (COVID-19), which is fatal in many cases, and is characterized by a cytokine release syndrome (CRS). Great efforts are currently being made to block the signal transduction pathway of pro-inflammatory cytokines in order to control this "cytokine storm" and rescue severely affected patients. Consequently, possible treatments for cytokine-mediated hyperinflammation, preferably within approved safe therapies, are urgently being researched to reduce rising mortality. One approach to inhibit proinflammatory cytokine release is to activate the cholinergic anti-inflammatory pathway through nicotinic acetylcholine receptors (α7nAchR). Nicotine, an exogenous α7nAchR agonist, is clinically used in ulcerative colitis to counteract inflammation. We have found epidemiological evidence, based on recent clinical SARS-CoV-2 studies in China, that suggest that smokers are statistically less likely to be hospitalized. In conclusion, our hypothesis proposes that nicotine could constitute a novel potential CRS therapy in severe SARS-CoV-2 patients.

Title: Cytokine Release Syndrome (CRS) and Nicotine in COVID-19 Patients: Trying to Calm the Storm Content: SARS-CoV-2 is a new coronavirus that has caused a worldwide pandemic. It causes severe acute respiratory syndrome (COVID-19), which is fatal in many cases, and is characterized by a cytokine release syndrome (CRS). Great efforts are currently being made to block the signal transduction pathway of pro-inflammatory cytokines in order to control this “cytokine storm” and rescue severely affected patients. Consequently, possible treatments for cytokine-mediated hyperinflammation, preferably within approved safe therapies, are urgently being researched to reduce rising mortality. One approach to inhibit proinflammatory cytokine release is to activate the cholinergic anti-inflammatory pathway through nicotinic acetylcholine receptors (α7nAchR). Nicotine, an exogenous α7nAchR agonist, is clinically used in ulcerative colitis to counteract inflammation. We have found epidemiological evidence, based on recent clinical SARS-CoV-2 studies in China, that suggest that smokers are statistically less likely to be hospitalized. In conclusion, our hypothesis proposes that nicotine could constitute a novel potential CRS therapy in severe SARS-CoV-2 patients.

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: Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality Content: Since December 2019, a viral pneumonia, named coronavirus disease 2019 (COVID-19), from Wuhan, China, has swept the world. Although the case fatality rate is not high, the number of people infected is large and there is still a large number of patients dying. With the collation and publication of more and more clinical data, a large number of data suggest that there are mild or severe cytokine storms in severe patients, which is an important cause of death. Therefore, treatment of the cytokine storm has become an important part of rescuing severe COVID-19 patients. Interleukin-6 (IL-6) plays an important role in cytokine release syndrome. If it is possible to block the signal transduction pathway of IL-6, it is expected to become a new method for the treatment of severe COVID-19 patients. Tocilizumab is an IL-6 receptor (IL-6R) blocker that can effectively block the IL-6 signal transduction pathway and thus is likely to become an effective drug for patients with severe COVID-19.