Question: what evidence is there for dexamethasone as a treatment for COVID-19?

Title: Transcatheter drug delivery through bronchial artery for COVID-19: is it fiction or could it come true? Content: More than 1,200 active or recruiting clinical trials for novel coronavirus disease 2019 (COVID-19) treatments and vaccines are registered. Many drugs have shown promise for treatment of COVID-19. Nevertheless, up to date, no drugs have been confirmed as a definitive treatment for COVID-19. Trials such as the SOLIDARITY and RECOVERY are ongoing, and first results were announced in favour of therapy with dexamethasone with a significant trend showing greatest benefit among those patients requiring ventilation. The drawbacks of these trials include exposing the patients to drugs with well-documented systemic adverse effects or unknown complications of novel therapies without proof of clinical benefit. We present here the hypothesis that bronchial artery infusion could be an alternative for systemic drug infusion in COVID-19 trials with superadded benefits of high drug concentration and low systemic adverse effects. The concept of this idea has many uncertainties and no current clinical data to support. Perhaps, the technique should be first applied in animal models to determine its safety and calculate the effective dose of the drugs. Guidelines and reviews of pharmacotherapy for COVID-19 should be implemented for this fiction to come true.

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: Role of corticosteroid in the management of COVID-19: A systemic review and a Clinician’s perspective Content: BACKGROUND AND AIMS: Interest in corticosteroid therapy in COVID-19 has been rekindled after the results from Randomized Evaluation of COVid-19 thERapY (RECOVERY) Trial. However, the World health Organization has not recommended corticosteroid in the treatment of COVID-19. We sought to conduct a systematic review on the role of corticosteroid in the management of patients of COVID-19. METHODS: A systematic electronic search of PubMed, Cochrane and MedRxiv database using specific keywords was made up till June 17, 2020. Full text of all the original articles with supplementary appendix that fulfilled the inclusion criteria were retrieved and a detailed analysis of results were represented. RESULTS: Of the 5 studies (4 retrospective studies and 1 quasi-prospective study) conducted for evaluating the role of corticosteroids, 3 studies have shown benefit, while 2 studies shown no benefit and there was a suggestion of significant harm in critical cases in one sub-study. RECOVERY trial is the only randomized controlled trial that has shown a significant reduction of death by 35% in ventilated patients and by 20% amongst patients on supplemental oxygen therapy with the dexamethasone, although no benefit was observed in mild cases. CONCLUSIONS: While the results from retrospective studies are heterogenous and difficult to infer of a definitive protective benefit with corticosteroids, RECOVERY trial found a significantly better outcome with dexamethasone, mostly in severe cases. Nonetheless, more studies are needed to replicate the outcome shown in RECOVERY trial for a substantial conclusion.

Title: Role of corticosteroid in the management of COVID-19: A systemic review and a Clinician's perspective Content: BACKGROUND AND AIMS: Interest in corticosteroid therapy in COVID-19 has been rekindled after the results from Randomized Evaluation of COVid-19 thERapY (RECOVERY) Trial. However, the World health Organization has not recommended corticosteroid in the treatment of COVID-19. We sought to conduct a systematic review on the role of corticosteroid in the management of patients of COVID-19. METHODS: A systematic electronic search of PubMed, Cochrane and MedRxiv database using specific keywords was made up till June 17, 2020. Full text of all the original articles with supplementary appendix that fulfilled the inclusion criteria were retrieved and a detailed analysis of results were represented. RESULTS: Of the 5 studies (4 retrospective studies and 1 quasi-prospective study) conducted for evaluating the role of corticosteroids, 3 studies have shown benefit, while 2 studies shown no benefit and there was a suggestion of significant harm in critical cases in one sub-study. RECOVERY trial is the only randomized controlled trial that has shown a significant reduction of death by 35% in ventilated patients and by 20% amongst patients on supplemental oxygen therapy with the dexamethasone, although no benefit was observed in mild cases. CONCLUSIONS: While the results from retrospective studies are heterogenous and difficult to infer of a definitive protective benefit with corticosteroids, RECOVERY trial found a significantly better outcome with dexamethasone, mostly in severe cases. Nonetheless, more studies are needed to replicate the outcome shown in RECOVERY trial for a substantial conclusion.

Title: A critical evaluation of glucocorticoids in the management of severe COVID-19 Content: The viral infection by SARS-CoV-2 has irrevocably altered the life of the majority of human beings, challenging national health systems worldwide, and pushing researchers to rapidly find adequate preventive and treatment strategies. No therapies have been shown effective with the exception of dexamethasone, a glucocorticoid that was recently proved to be the first life-saving drug in this disease. Remarkably, around 20 % of infected people develop a severe form of COVID-19, giving rise to respiratory and multi-organ failures requiring subintensive and intensive care interventions. This phenomenon is due to an excessive immune response that damages pulmonary alveoli, leading to a cytokine and chemokine storm with systemic effects. Indeed glucocorticoids' role in regulating this immune response is controversial, and they have been used in clinical practice in a variety of countries, even without a previous clear consensus on their evidence-based benefit.

Title: Short-Term Dexamethasone in Sars-CoV-2 Patients. Content: BACKGROUND Dexamethasone, a synthetic glucocorticoid, has anti-inflammatory and immunosuppressive properties. There is a hyperinflammatory response involved in the clinical course of patients with pneumonia due to SARS-CoV-2. To date, there has been no definite therapy for COVID-19. We reviewed the charts of SARS-CoV-2 patients with pneumonia and moderate to severely elevated CRP and worsening hypoxemia who were treated with early, short-term dexamethasone. METHODS We describe a series of 21 patients who tested positive for SARS-CoV-2 and were admitted to The Miriam Hospital in Providence, RI, and were treated with a short course of dexamethasone, either alone or in addition to current investigative therapies. RESULTS CRP levels decreased significantly following the start of dexamethasone from mean initial levels of 129.52 to 40.73 mg/L at time of discharge. 71% percent of the patients were discharged home with a mean length of stay of 7.8 days. None of the patients had escalation of care, leading to mechanical ventilation. Two patients were transferred to inpatient hospice facilities on account of persistent hypoxemia, in line with their documented goals of care. CONCLUSIONS A short course of systemic corticosteroids among inpatients with SARS-CoV-2 with hypoxic respiratory failure was well tolerated, and most patients had improved outcomes. This limited case series may not offer concrete evidence towards the benefit of corticosteroids in COVID-19. However, patients' positive response to short-term corticosteroids demonstrates that they may help blunt the severity of inflammation and prevent a severe hyperinflammatory phase, in turn reducing the length of stay, ICU admissions, and healthcare costs.

Title: Short-Term Corticosteroids in SARS-CoV2 Patients: Hospitalists' Perspective Content: Background: Dexamethasone, a synthetic glucocorticoid, has anti-inflammatory and immunosuppressive properties. There is a hyperinflammatory response involved in the clinical course of patients with pneumonia due to SARS-CoV2. To date, there has been no definite therapy for COVID-19. We reviewed the charts of SARS-CoV2 patients with pneumonia and moderate to severely elevated CRP and worsening hypoxemia who were treated with early, short-term dexamethasone. Methods: We describe a series of 21 patients who tested positive for SARS-CoV2 and were admitted to The Miriam Hospital in Providence and were treated with a short course of dexamethasone, either alone or in addition to current investigative therapies. Results: CRP levels decreased significantly following the start of dexamethasone from mean initial levels of 129.52 to 40.73 mg/L at time of discharge. 71% percent of the patients were discharged home with a mean length of stay of 7.8 days. None of the patients had escalation of care, leading to mechanical ventilation. Two patients were transferred to inpatient hospice facilities on account of persistent hypoxemia, in line with their documented goals of care. Conclusions: A short course of systemic corticosteroids among inpatients with SARS-CoV2 with hypoxic respiratory failure was well tolerated, and most patients had improved outcomes. This limited case series may not offer concrete evidence towards the benefit of corticosteroids in COVID-19. However, patients positive response to short-term corticosteroids demonstrates that they may help blunt the severity of inflammation and prevent a severe hyperinflammatory phase, in turn reducing the length of stay, ICU admissions, and healthcare costs.

Title: COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting? Content: Given the current SARS-CoV-2 (COVID-19) pandemic, the availability of reliable information for clinicians and patients is paramount. There have been a number of reports stating that non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids may exacerbate symptoms in COVID-19 patients. Therefore, this review aimed to collate information available in published articles to identify any evidence behind these claims with the aim of advising clinicians on how best to treat patients. This review found no published evidence for or against the use of NSAIDs in COVID-19 patients. Meanwhile, there appeared to be some evidence that corticosteroids may be beneficial if utilised in the early acute phase of infection, however, conflicting evidence from the World Health Organisation surrounding corticosteroid use in certain viral infections means this evidence is not conclusive. Given the current availability of literature, caution should be exercised until further evidence emerges surrounding the use of NSAIDs and corticosteroids in COVID-19 patients.

Title: Dexamethasone for COVID-19? Not so fast Content: Recent announcements indicated, without sharing any distinct published set of results, that the corticosteroid dexamethasone may reduce mortality of severe COVID-19 patients only. The recent Coronavirus [severe acute respiratory syndrome (SARS)-CoV-2]-associated multiorgan disease, called COVID-19, has high morbidity and mortality due to autoimmune destruction of the lungs stemming from the release of a storm of pro-inflammatory cytokines. Defense against this Corona virus requires activated T cells and specific antibodies. Instead, cytokines are responsible for the serious sequelae of COVID-19 that damage the lungs. Dexamethasone is a synthetic corticosteroid approved by the FDA 1958 as a broad-spectrum immunosuppressor and it is about 30 times as active and with longer duration of action (2-3 days) than cortisone. Dexamethasone would limit the production of and damaging effect of the cytokines, but will also inhibit the protective function of T cells and block B cells from making antibodies, potentially leading to increased plasma viral load that will persist after a patient survives SARS. Moreover, dexamethasone would block macrophages from clearing secondary, nosocomial, infections. Hence, dexamethasone may be useful for the short-term in severe, intubated, COVID-19 patients, but could be outright dangerous during recovery since the virus will not only persist, but the body will be prevented from generating protective antibodies. Instead, a pulse of intravenous dexamethasone may be followed by administration of nebulized triamcinolone (6 times as active as cortisone) to concentrate in the lungs only. These corticosteroids could be given together with the natural flavonoid luteolin because of its antiviral and anti-inflammatory properties, especially its ability to inhibit mast cells, which are the main source of cytokines in the lungs. At the end, we should remember that "The good physician treats the disease; the great physician treats the patient who has the disease" [Sir William Osler's (1849-1919)].

Title: Dexamethasone for COVID-19? Not so fast. Content: Recent announcements indicated, without sharing any distinct published set of results, that the corticosteroid dexamethasone may reduce mortality of severe COVID-19 patients only. The recent Coronavirus [severe acute respiratory syndrome (SARS)-CoV-2]-associated multiorgan disease, called COVID-19, has high morbidity and mortality due to autoimmune destruction of the lungs stemming from the release of a storm of pro-inflammatory cytokines. Defense against this Corona virus requires activated T cells and specific antibodies. Instead, cytokines are responsible for the serious sequelae of COVID-19 that damage the lungs. Dexamethasone is a synthetic corticosteroid approved by the FDA 1958 as a broad-spectrum immunosuppressor and it is about 30 times as active and with longer duration of action (2-3 days) than cortisone. Dexamethasone would limit the production of and damaging effect of the cytokines, but will also inhibit the protective function of T cells and block B cells from making antibodies, potentially leading to increased plasma viral load that will persist after a patient survives SARS. Moreover, dexamethasone would block macrophages from clearing secondary, nosocomial, infections. Hence, dexamethasone may be useful for the short-term in severe, intubated, COVID-19 patients, but could be outright dangerous during recovery since the virus will not only persist, but the body will be prevented from generating protective antibodies. Instead, a pulse of intravenous dexamethasone may be followed by administration of nebulized triamcinolone (6 times as active as cortisone) to concentrate in the lungs only. These corticosteroids could be given together with the natural flavonoid luteolin because of its antiviral and anti-inflammatory properties, especially its ability to inhibit mast cells, which are the main source of cytokines in the lungs. At the end, we should remember that "The good physician treats the disease; the great physician treats the patient who has the disease" [Sir William Osler's (1849-1919)].

Title: A critical evaluation of glucocorticoids in the treatment of severe COVID-19 Content: The viral infection by SARS-CoV-2, has revolutionized the life of the majority of human beings, challenging national health systems worldwide, and pushing researchers to rapidly find adequate preventive and treatment strategies. No therapies have been shown effective, with the exception of dexamethasone, a glucocorticoid that was recently proved to be the first life-saving drug in this disease. Remarkably, around 20% of infected people develop a severe form of COVID-19, giving rise to respiratory and multi-organ failures requiring subintensive and intensive care interventions. This phenomenon is due to an excessive immune response that damages pulmonary alveoli, leading to a cytokine and chemokine storm with systemic effects. Indeed glucocorticoids’ role in regulating this immune response is controversial, and they have been used in clinical practice in a variety of countries, even without a previous clear consensus on their evidence-based benefit.

Title: Short-Term Dexamethasone in Sars-CoV-2 Patients Content: BACKGROUND: Dexamethasone, a synthetic glucocorticoid, has anti-inflammatory and immunosuppressive properties There is a hyperinflammatory response involved in the clinical course of patients with pneumonia due to SARS-CoV-2 To date, there has been no definite therapy for COVID-19 We reviewed the charts of SARS-CoV-2 patients with pneumonia and moderate to severely elevated CRP and worsening hypoxemia who were treated with early, short-term dexamethasone METHODS: We describe a series of 21 patients who tested positive for SARS-CoV-2 and were admitted to The Miriam Hospital in Providence, RI, and were treated with a short course of dexamethasone, either alone or in addition to current investigative therapies RESULTS: CRP levels decreased significantly following the start of dexamethasone from mean initial levels of 129 52 to 40 73 mg/L at time of discharge 71% percent of the patients were discharged home with a mean length of stay of 7 8 days None of the patients had escalation of care, leading to mechanical ventilation Two patients were transferred to inpatient hospice facilities on account of persistent hypoxemia, in line with their documented goals of care CONCLUSIONS: A short course of systemic corticosteroids among inpatients with SARS-CoV-2 with hypoxic respiratory failure was well tolerated, and most patients had improved outcomes This limited case series may not offer concrete evidence towards the benefit of corticosteroids in COVID-19 However, patients' positive response to short-term corticosteroids demonstrates that they may help blunt the severity of inflammation and prevent a severe hyperinflammatory phase, in turn reducing the length of stay, ICU admissions, and healthcare costs

Title: Pros and cons of corticosteroid therapy for COVID-19 patients Content: In December 2019, an outbreak of severe pneumonia was reported in Wuhan, China. Later described as COVID-19 (coronavirus disease 2019), this infection caused by a virus from the Coronaviridae family (SARS-CoV-2) has spread globally. Effective therapies for this new disease are urgently needed. In this short communication, we will evaluate the use of corticosteroids as an adjunctive pharmacological therapy in the management of COVID-19 and describe its pros and cons in light of the latest available evidence.

Title: Use of Corticosteroids in Coronavirus Disease 2019 Pneumonia: A Systematic Review of the Literature Content: The aim was to investigate the effectiveness of glucocorticoid therapy in patients with COVID-19. A systematic search of the literature across nine databases was conducted from inception until 15th March 2020, following the PRISMA guidelines. Patients with a validated diagnosis of COVID-19 and using corticosteroids were included, considering all health outcomes. Four studies with 542 Chinese participants were included. Two studies reported negative findings regarding the use of corticosteroids in patients with COVID-19, i.e., corticosteroids had a detrimental impact on clinical outcomes. One study reported no significant association between the use of corticosteroids and clinical outcomes. However, one study, on 201 participants with different stages of pneumonia due to COVID-19, found that in more severe forms, the administration of methylprednisolone significantly reduced the risk of death by 62%. The literature to date does not fully support the routine use of corticosteroids in COVID-19, but some findings suggest that methylprednisolone could lower mortality rate in more severe forms of the condition.

Title: Pharmacologicaltreatment of COVID-19: lights and shadows Content: At the end of December 2019, a novel coronavirus, the severe acute respiratory syndrome coronavirus 2, caused an outbreak of pneumonia spreading from Wuhan, Hubei province, to the whole country of China and then the entire world, forcing the World Health Organization to make the assessment that the coronavirus disease (COVID-19) can be characterized as a pandemic, the first ever caused by a coronavirus. To date, clinical evidence and guidelines based on reliable data and randomized clinical trials for the treatment of COVID-19 are lacking. In the absence of definitive management protocols, many treatments for COVID-19 are currently being evaluated and tested worldwide. Some of these options were soon abandoned due to ineffectiveness, while others showed promising results. The basic treatments are mainly represented by antiviral drugs, even if the evidence is not satisfactory. Among the antivirals, the most promising appears to be remdesivir. Corticosteroids and tocilizumab seem to guarantee positive results in selected patients so far, although the timing of starting therapy and the most appropriate therapeutic schemes remain to be clarified. Efficacy of the other drugs is still uncertain, and they are currently used as a cocktail of treatments in the absence of definitive guidelines. What will represent the real solution to the enormous problem taking place worldwide is the identification of a safe and effective vaccine, for which enormous efforts and investments are underway.

Title: Therapeutic Management of COVID-19 Patients: A systematic review Content: Background: SARS-CoV-2 is the cause of the COVID-19 that has been declared a global pandemic by the WHO in 2020. The COVID-19 treatment guidelines vary in each country, and yet there is no approved therapeutic for COVID-19. Aims of the study: this review aimed to report any evidence of therapeutics used for the management of COVID-19 patients in clinical practice since the emergence of the virus. Methods: A systematic review protocol was developed based on PRISMA Statement. Articles for review were selected from electronic databases (Embase, Medline and Google Scholar). Readily accessible peer-reviewed full articles in English published from December 1 st , 2019 to March 26 th , 2020 were included. The search terms included combinations of: COVID, SARS-COV-2, glucocorticoids, convalescent plasma, antiviral, antibacterial. There were no restrictions on the type of study design eligible for inclusion. Results: As of March 26, 2020, of the initial manuscripts identified (n=449) articles. Forty-one studies were included, of which clinical trials (n=3), (case reports n=7), case series (n=10), retrospective (n=11) and prospective (n=10) observational studies. Thirty-six studies were conducted in China (88%). The most common mentioned and reported medicine in this systematic review was corticosteroids (n=25), followed by Lopinavir (n=21) and oseltamivir (n=16). Conclusions: This is the first systematic review up to date related to the therapeutics used in COVID-19 patients. Only forty-one research articles on COVID-19 and therapeutics were found eligible to be included, most conducted in China, corticosteroid therapy was found to be the most used medicine in these studies.

Title: Therapeutic Management of COVID-19 Patients: A systematic review Content: Abstract Background SARS-CoV-2 is the causative agent of COVID-19; that has been declared a global pandemic by the WHO in 2020. The COVID-19 treatment guidelines vary in each country, and yet there is no approved therapeutic for COVID-19. Aims of the study this review aimed to report any evidence of therapeutics used for the management of COVID-19 patients in clinical practice since the emergence of the virus. Methods A systematic review protocol was developed based on PRISMA Statement. Articles for review were selected from electronic databases (Embase, Medline and Google Scholar). Readily accessible peer-reviewed, full articles in English published from December 1st , 2019 to March 26th , 2020 were included. The search terms included combinations of: COVID, SARS-COV-2, glucocorticoids, convalescent plasma, antiviral and antibacterial. There were no restrictions on the type of study design eligible for inclusion. Results As of March 26th, 2020, of the initial manuscripts identified (n=449); forty-one studies were included. These consisted of clinical trials (n=3), case reports (n=7), case series (n=10), retrospective (n=11) and prospective (n=10) observational studies. Thirty-six studies were conducted in China (88%). The most commonly reported medicine in this systematic review was corticosteroids (n=25), followed by Lopinavir (n=21) and Oseltamivir (n=16). Conclusions This is the first systematic review to date related to the therapeutics used in COVID-19 patients. Only 41 research articles on COVID-19 and therapeutics were found eligible to be included, most conducted in China. Corticosteroid therapy was found to be the most studied medicine in the literature.

Title: Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report Content: Background: Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death. Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results: 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Conclusions: In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support.

Title: IL-6 Inhibitors in the Treatment of Serious COVID-19: A Promising Therapy? Content: At present, there are no proven agents for treatment of coronavirus disease (COVID-19). The available evidence has not allowed guidelines to clearly recommend any drugs outside the context of clinical trials. The novel coronavirus SARS-CoV-2 that causes COVID-19 invokes a hyperinflammatory state driven by multiple cells and mediators like interleukin (IL)-1, IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNFα), etc. Considering the proven role of cytokine dysregulation in causing this hyperinflammation in the lungs with IL-6 being a key driver, particularly in seriously ill COVID-19 patients, it is crucial to further explore selective cytokine blockade with drugs like the IL-6 inhibitors tocilizumab, sarilumab, and siltuximab. These targeted monoclonal antibodies can dampen the downstream IL-6 signaling pathways, which can lead to decreased cell proliferation, differentiation, oxidative stress, exudation, and improve clinical outcomes in patients with evident features of cytokine-driven inflammation like persistent fever, dyspnea and elevated markers. Preliminary evidence has come for tocilizumab from some small studies, and interim analysis of a randomized controlled trial; the latter also being available for sarilumab. International guidelines do include IL-6 inhibitors as one of the options available for severe or critically ill patients. There has been increased interest in evaluating these drugs with a series of clinical trials being registered and conducted in different countries. The level of investigation though perhaps needs to be further intensified as there is a need to focus on therapeutic options that can prove to be 'life-saving' as the number of COVID-19 fatalities worldwide keeps increasing alarmingly. IL-6 inhibitors could be one such treatment option, with generation of more evidence and completion of a larger number of systematic studies.

Title: COVID-19: An Update on the Epidemiological, Clinical, Preventive and Therapeutic Evidence and Guidelines of Integrative Chinese-Western Medicine for the Management of 2019 Novel Coronavirus Disease Content: As of 22 February 2020, more than 77662 cases of confirmed COVID-19 have been documented globally with over 2360 deaths. Common presentations of confirmed cases include fever, fatigue, dry cough, upper airway congestion, sputum production, shortness of breath, myalgia/arthralgia with lymphopenia, prolonged prothrombin time, elevated C-reactive protein, and elevated lactate dehydrogenase. The reported severe/critical case ratio is approximately 7-10% and median time to intensive care admission is 9.5-10.5 days with mortality of around 1-2% varied geographically. Similar to outbreaks of other newly identified virus, there is no proven regimen from conventional medicine and most reports managed the patients with lopinavir/ritonavir, ribavirin, beta-interferon, glucocorticoid and supportive treatment with remdesivir undergoing clinical trial. In China, Chinese medicine is proposed as a treatment option by national and provincial guidelines with substantial utilization. We reviewed the latest national and provincial clinical guidelines, retrospective cohort studies, and case series regarding the treatment of COVID-19 by add-on Chinese medicine. We have also reviewed the clinical evidence generated from SARS and H1N1 management with hypothesized mechanisms and latest in silico findings to identify candidate Chinese medicines for the consideration of possible trials and management. Given the paucity of strongly evidence-based regimens, the available data suggest that Chinese medicine could be considered as an adjunctive therapeutic option in the management of COVID-19.

Title: COVID-19: An Update on the Epidemiological, Clinical, Preventive and Therapeutic Evidence and Guidelines of Integrative Chinese-Western Medicine for the Management of 2019 Novel Coronavirus Disease. Content: As of 22 February 2020, more than 77662 cases of confirmed COVID-19 have been documented globally with over 2360 deaths. Common presentations of confirmed cases include fever, fatigue, dry cough, upper airway congestion, sputum production, shortness of breath, myalgia/arthralgia with lymphopenia, prolonged prothrombin time, elevated C-reactive protein, and elevated lactate dehydrogenase. The reported severe/critical case ratio is approximately 7-10% and median time to intensive care admission is 9.5-10.5 days with mortality of around 1-2% varied geographically. Similar to outbreaks of other newly identified virus, there is no proven regimen from conventional medicine and most reports managed the patients with lopinavir/ritonavir, ribavirin, beta-interferon, glucocorticoid and supportive treatment with remdesivir undergoing clinical trial. In China, Chinese medicine is proposed as a treatment option by national and provincial guidelines with substantial utilization. We reviewed the latest national and provincial clinical guidelines, retrospective cohort studies, and case series regarding the treatment of COVID-19 by add-on Chinese medicine. We have also reviewed the clinical evidence generated from SARS and H1N1 management with hypothesized mechanisms and latest in silico findings to identify candidate Chinese medicines for the consideration of possible trials and management. Given the paucity of strongly evidence-based regimens, the available data suggest that Chinese medicine could be considered as an adjunctive therapeutic option in the management of COVID-19.

Title: IL-6 Inhibitors in the Treatment of Serious COVID-19: A Promising Therapy? Content: At present, there are no proven agents for treatment of coronavirus disease (COVID-19). The available evidence has not allowed guidelines to clearly recommend any drugs outside the context of clinical trials. The novel coronavirus SARS-CoV-2 that causes COVID-19 invokes a hyperinflammatory state driven by multiple cells and mediators like interleukin (IL)-1, IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNFα), etc. Considering the proven role of cytokine dysregulation in causing this hyperinflammation in the lungs with IL-6 being a key driver, particularly in seriously ill COVID-19 patients, it is crucial to further explore selective cytokine blockade with drugs like the IL-6 inhibitors tocilizumab, sarilumab, and siltuximab. These targeted monoclonal antibodies can dampen the downstream IL-6 signaling pathways, which can lead to decreased cell proliferation, differentiation, oxidative stress, exudation, and improve clinical outcomes in patients with evident features of cytokine-driven inflammation like persistent fever, dyspnea and elevated markers. Preliminary evidence has come for tocilizumab from some small studies, and interim analysis of a randomized controlled trial; the latter also being available for sarilumab. International guidelines do include IL-6 inhibitors as one of the options available for severe or critically ill patients. There has been increased interest in evaluating these drugs with a series of clinical trials being registered and conducted in different countries. The level of investigation though perhaps needs to be further intensified as there is a need to focus on therapeutic options that can prove to be ‘life-saving’ as the number of COVID-19 fatalities worldwide keeps increasing alarmingly. IL-6 inhibitors could be one such treatment option, with generation of more evidence and completion of a larger number of systematic studies.

Title: The use of corticosteroids for COVID-19 infection Content: The SARS-CoV-2 pandemic is continuing relentlessly in many parts of the world and has resulted in the outpouring of literature on various aspects of the infection, including studies and recommendations regarding the optimal treatment of infected patients. Not surprisingly, the use of corticosteroids in the management of such patients has featured prominently in many of these publications. There is considerable debate in the literature as to the likely benefits, as well as the potential detrimental effects of corticosteroid therapy in general viral respiratory infections and, in particular, COVID-19 infections. While the definitive answer may need to await the results of ongoing randomised, controlled trials recent studies suggest that corticosteroid use in COVID-19 cases with hypoxaemia may benefit from low-dose corticosteroid therapy.

Title: Initial experience with short-course corticosteroids in a small cohort of adults with severe COVID-19 in a tertiary care hospital in India Content: Abstract Severe COVID 19 disease is associated with high morbidity and mortality with limited therapeutic options. The role of glucocorticoids in treatment of COVID 19 has been riddled with controversy. The study site has been using glucocorticoids in patients with severe COVID 19 since the first few patients of COVID 19 that were admitted. In the initial cohort of 7 patients with severe COVID disease, use of methylprednisolone in a dose of 30 mg twice daily was associated with rapid improvement in oxygenation and decline in CRP levels. While six patients made a complete clinical recovery, one patient died. There were no secondary infections.

Title: Letter to the editor: efficacy of different methods of combination regimen administrations including dexamethasone, intravenous immunoglobulin, and interferon-beta to treat critically ill COVID-19 patients: a structured summary of a study protocol for a randomized controlled trial Content: OBJECTIVES: There is little information about Coronavirus Disease 2019 (COVID-19) management for critically ill patients. Most of these patients develop acute respiratory distress syndrome (ARDS) due to excessive inflammatory response and the ensuing cytokine storm. Anti-inflammatory drugs including corticosteroids can be used to effectively reduce the effect of this cytokine storm and lung damage. However, corticosteroids can have side effects, so simultaneous administration of immunoglobulin (IV-IG) and interferon-beta can help manage treatment using corticosteroids. Therefore, we designed a trial to test our hypothesis that early administration of dexamethasone in combination with IV-IG and interferon-beta can reduce the effect of the cytokine storm in critically ill patients COVID-19. TRIAL DESIGN: A phase two multi-center randomized controlled trial (RCT) with three parallel arms (1:1:1 ratio). PARTICIPANTS: They will be hospitalized patients with severe COVID-19 who have positive RT-PCR test and have blood oxygen saturation levels (SpO2) less than 90% and respiratory rate higher than 24 per minute or have involvement of more than 50% of their lung when viewed using computed tomography (CT)-scan. The age range of patients will be 18-70 years old. EXCLUSION CRITERIA: the need for intubation; allergy, intolerance, or contraindication to any study drug including dexamethasone, IV-IG, and interferon-beta; pregnancy or lactation; known HIV positive or active hepatitis B or C. The study will be conducted in several hospitals of the Golestan province, Iran. INTERVENTION AND COMPARATOR: The study subjects will be randomly allocated to three treatment arms: two experimental groups (two arms: Intervention 1 and Intervention 2) and one Control Group, which will be matched for age and sex using frequency matching method. Each eligible patient in the control arm will receive the standard treatment for COVID-19 based on WHO guidelines and the Ministry of the Health and Medical Education (MOHME) of Iran. Each patient in the Intervention Group 1 will receive the standard treatment for COVID-19 and dexamethasone, at the first 24 hours' time of admission. The intervention begins with the administration of dexamethasone based on the SpO2 levels. If the level of SpO2 does not improve after 24 hours, IV-IG (400 mg/kg once daily for 5 days) and interferon-beta (7 doses every other day) will be prescribed along with dexamethasone administration. In Intervention Group 2, the administration of dexamethasone will be started within the first 24 hours' time of admission and will be continued for 48-72 hours and then the SpO2 level will be checked. Then, if the level of SpO2 has not improved after that time, IV-IG and interferon-beta will be prescribed as the same dosage as Group 1. If the percentages of the SpO2 level are between 85 and 90/ 80 and 85/ 75 and 80/ less than 75, the dosages will be 4 mg every 12 hours/ 4 mg every 8 hours/ 8 mg every 12 hours/ 8 mg every 8 hours, respectively. According to the WHO recommendation, all participants will have the best available supportive care with full monitoring. MAIN OUTCOMES: Primary: An increase in the SpO2 level to reach more than 90% in each case, which will be assessed by the oximeter. Secondary: The duration of hospital stays; intubation status and the percentage of patients who are free of mechanical ventilation; the mortality rates during hospitalization and one month after the admission time. RANDOMISATION: Participants will be allocated into either control or intervention groups with a 1:1:1 allocation ratio using a computer random number generator to generate a table of random numbers for simple randomization. BLINDING (MASKING): The project's principal investigator (PI) is unblinded. However, the PI will not analyse the data and interpret the results. An unblinded researcher (a pharmacist) will cover the drug's bottles with aluminium foil and prepare them interventions and control drugs in a syringe with a code so that patients are blinded. This person will have no patients contact. The staff and nurses, caring for the patients, will be unblinded for each study group due to the nature of this study. The staff that take outcome measurements will be blinded. The laboratory technicians will also be blinded as well as the statistical team. These study statisticians will have access to coded data and will analyse the data labelled as group X, group Y, and group Z. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The target sample size will be 105 critically ill COVID-19 patients, who will be allocated randomly to the three trial arms with 35 patients in each group. TRIAL STATUS: Recruitment is ongoing. The study began on April 18 2020 and will be completed June 19 2020. This summary describes protocol version 1; April 2 2020. TRIAL REGISTRATION: https://www.irct.ir/. Identifier: IRCT20120225009124N4 version 1; Registration date: April 2 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The full protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.

Title: Therapeutic potential of ciclesonide inahalation for COVID-19 pneumonia: Report of three cases Content: No specific and effective anti-viral treatment has been approved for COVID-19 so far. Systemic corticosteroid has been sometimes administered to severe infectious diseases combined with the specific treatment. However, as lack of the specific anti-SARS-CoV-2 drug, systemic steroid treatment has not been recommended for COVID-19. We report here three cases of the COVID-19 pneumonia successfully treated with ciclesonide inhalation. Rationale of the treatment is to mitigate the local inflammation with inhaled steroid that stays in the lung and to inhibit proliferation of the virus by antiviral activity. Larger and further studies are warranted to confirm the result of these cases.

Title: COVID-19-associated ARDS treated with DEXamethasone (CoDEX): Study design and rationale for a randomized trial. Content: OBJECTIVES: The infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) spreads worldwide and is considered a pandemic. The most common manifestation of SARS-CoV2 infection (Coronavirus disease 2019 - COVID-19) is viral pneumonia with varying degrees of respiratory compromise and up to 40% of hospitalized patients might develop Acute Respiratory Distress Syndrome (ARDS). Several clinical trials evaluated the role of corticosteroids in non-COVID-19 ARDS with conflicting results. We designed a trial to evaluate the effectiveness of early intravenous dexamethasone administration on the number of days alive and free of mechanical ventilation within 28 days after randomization in adult patients with moderate or severe ARDS due to confirmed or probable COVID-19. METHODS: This is a pragmatic, prospective, randomized, stratified, multicenter, open-label, controlled trial including 350 patients with early-onset (less than 48h before randomization) moderate or severe ARDS, defined by the Berlin criteria, due to COVID-19. Eligible patients will be randomly allocated to either standard treatment plus dexamethasone (intervention group) or standard treatment without dexamethasone (control group). Patients in the intervention group will receive dexamethasone 20mg IV once daily for 5 days, followed by dexamethasone 10mg IV once daily for additional 5 days or until Intensive Care Unit (ICU) discharge, whichever occurs first. The primary outcome is ventilator-free days within 28 days after randomization, defined as days alive and free from invasive mechanical ventilation. Secondary outcomes are all-cause mortality rates at day 28, evaluation of the clinical status at day 15 assessed with a 6-level ordinal scale, mechanical ventilation duration from randomization to day 28, Sequential Organ Failure Assessment (SOFA) Score evaluation at 48h, 72h and 7 days and ICU-free days within 28. ETHICS AND DISSEMINATION: This trial was approved by the Brazilian National Committee of Ethics in Research (Comissao Nacional de Etica em Pesquisa - CONEP) and National Health Surveillance Agency (ANVISA). An independent data monitoring committee will perform interim analyses and evaluate adverse events throughout the trial. Results will be submitted for publication after enrolment and follow-up are complete.

Title: Letter to the editor: efficacy of different methods of combination regimen administrations including dexamethasone, intravenous immunoglobulin, and interferon-beta to treat critically ill COVID-19 patients: a structured summary of a study protocol for a randomized controlled trial Content: OBJECTIVES: There is little information about Coronavirus Disease 2019 (COVID-19) management for critically ill patients. Most of these patients develop acute respiratory distress syndrome (ARDS) due to excessive inflammatory response and the ensuing cytokine storm. Anti-inflammatory drugs including corticosteroids can be used to effectively reduce the effect of this cytokine storm and lung damage. However, corticosteroids can have side effects, so simultaneous administration of immunoglobulin (IV-IG) and interferon-beta can help manage treatment using corticosteroids. Therefore, we designed a trial to test our hypothesis that early administration of dexamethasone in combination with IV-IG and interferon-beta can reduce the effect of the cytokine storm in critically ill patients COVID-19. TRIAL DESIGN: A phase two multi-center randomized controlled trial (RCT) with three parallel arms (1:1:1 ratio). PARTICIPANTS: They will be hospitalized patients with severe COVID-19 who have positive RT-PCR test and have blood oxygen saturation levels (SpO(2)) less than 90% and respiratory rate higher than 24 per minute or have involvement of more than 50% of their lung when viewed using computed tomography (CT)-scan. The age range of patients will be 18-70 years old. Exclusion criteria: the need for intubation; allergy, intolerance, or contraindication to any study drug including dexamethasone, IV-IG, and interferon-beta; pregnancy or lactation; known HIV positive or active hepatitis B or C. The study will be conducted in several hospitals of the Golestan province, Iran. INTERVENTION AND COMPARATOR: The study subjects will be randomly allocated to three treatment arms: two experimental groups (two arms: Intervention 1 and Intervention 2) and one Control Group, which will be matched for age and sex using frequency matching method. Each eligible patient in the control arm will receive the standard treatment for COVID-19 based on WHO guidelines and the Ministry of the Health and Medical Education (MOHME) of Iran. Each patient in the Intervention Group 1 will receive the standard treatment for COVID-19 and dexamethasone, at the first 24 hours’ time of admission. The intervention begins with the administration of dexamethasone based on the SpO(2) levels. If the level of SpO(2) does not improve after 24 hours, IV-IG (400 mg/kg once daily for 5 days) and interferon-beta (7 doses every other day) will be prescribed along with dexamethasone administration. In Intervention Group 2, the administration of dexamethasone will be started within the first 24 hours’ time of admission and will be continued for 48-72 hours and then the SpO(2) level will be checked. Then, if the level of SpO(2) has not improved after that time, IV-IG and interferon-beta will be prescribed as the same dosage as Group 1. If the percentages of the SpO(2) level are between 85 and 90/ 80 and 85/ 75 and 80/ less than 75, the dosages will be 4 mg every 12 hours/ 4 mg every 8 hours/ 8 mg every 12 hours/ 8 mg every 8 hours, respectively. According to the WHO recommendation, all participants will have the best available supportive care with full monitoring. MAIN OUTCOMES: Primary: An increase in the SpO(2) level to reach more than 90% in each case, which will be assessed by the oximeter. Secondary: The duration of hospital stays; intubation status and the percentage of patients who are free of mechanical ventilation; the mortality rates during hospitalization and one month after the admission time. RANDOMISATION: Participants will be allocated into either control or intervention groups with a 1:1:1 allocation ratio using a computer random number generator to generate a table of random numbers for simple randomization. BLINDING (MASKING): The project's principal investigator (PI) is unblinded. However, the PI will not analyse the data and interpret the results. An unblinded researcher (a pharmacist) will cover the drug’s bottles with aluminium foil and prepare them interventions and control drugs in a syringe with a code so that patients are blinded. This person will have no patients contact. The staff and nurses, caring for the patients, will be unblinded for each study group due to the nature of this study. The staff that take outcome measurements will be blinded. The laboratory technicians will also be blinded as well as the statistical team. These study statisticians will have access to coded data and will analyse the data labelled as group X, group Y, and group Z. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The target sample size will be 105 critically ill COVID-19 patients, who will be allocated randomly to the three trial arms with 35 patients in each group. TRIAL STATUS: Recruitment is ongoing. The study began on April 18 2020 and will be completed June 19 2020. This summary describes protocol version 1; April 2 2020. TRIAL REGISTRATION: https://www.irct.ir/. Identifier: IRCT20120225009124N4 version 1; Registration date: April 2 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The full protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.

Title: Routine antiemetic prophylaxis with dexamethasone during COVID-19: Should oncologists reconsider? Content: The ongoing pandemic caused by severe acute respiratory syndrome (SARS) coronavirus type 2 (SARS-CoV-2, also known as COVID-19) has caused unprecedented strain on the global healthcare system, causing thousands of deaths worldwide. Patients with underlying conditions such as cancer are at substantial risk of acquiring and dying from this novel coronavirus. Numerous reports have shown that infection with SARS-CoV-2 causes depletion of B- and T-lymphocytes, including CD4 and CD8 T-cells, and is associated with severe illness and death and that patients with higher lymphocyte levels may have better outcomes. Dexamethasone, a widely prescribed antiemetic for acute and delayed nausea and vomiting from a variety of cancer drugs, causes B and T cell depletion, which may augment immunosuppression. Since it seems that lymphocytes are vital in the immune response to novel coronavirus, oncologists should reconsider the routine use of prophylactic dexamethasone in uninfected patients, to avoid inducing lymphopenia, which may increase risk of infection or lead to inferior outcomes if a cancer patient subsequently becomes infected. Since many cancer drugs and malignant diseases inherently cause lymphopenia, further reduction of lymphocytes with dexamethasone should be avoided if possible and if safe and effective alternative antiemetics are available during the COVID-19 crisis.

Title: Heparin as a Therapy for COVID-19: Current Evidence and Future Possibilities Content: Coronavirus Disease 2019 (COVID-19), the clinical syndrome associated with infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has impacted nearly every country in the world. Despite an unprecedented focus of scientific investigation, there is a paucity of evidence-based pharmacotherapies against this disease. Due to this lack of data-driven treatment strategies, broad variations in practice patterns have emerged. Observed hypercoagulability in COVID-19 patients has created debate within the critical care community on the therapeutic utility of heparin. We seek to provide an overview of the data supporting the therapeutic use of heparin, both unfractionated and low molecular weight, as an anticoagulant for the treatment of SARS-CoV-2 infection. Additionally, we review preclinical evidence establishing biological plausibility for heparin and synthetic heparin-like drugs as therapies for COVID-19 through anti-viral and anti-inflammatory effects. Finally, we discuss known adverse effects and theoretical off-target effects that may temper enthusiasm for the adoption of heparin as a therapy in COVID-19 without confirmatory prospective randomized controlled trials. Despite previous failures of anticoagulants in critical illness, plausibility of heparin for COVID-19 is sufficiently robust to justify urgent randomized controlled trials to determine the safety and effectiveness of this therapy.

Title: Heparin as a Therapy for COVID-19: Current Evidence and Future Possibilities. Content: Coronavirus Disease 2019 (COVID-19), the clinical syndrome associated with infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has impacted nearly every country in the world. Despite an unprecedented focus of scientific investigation, there is a paucity of evidence-based pharmacotherapies against this disease. Due to this lack of data-driven treatment strategies, broad variations in practice patterns have emerged. Observed hypercoagulability in COVID-19 patients has created debate within the critical care community on the therapeutic utility of heparin. We seek to provide an overview of the data supporting the therapeutic use of heparin, both unfractionated and low molecular weight, as an anticoagulant for the treatment of SARS-CoV-2 infection. Additionally, we review preclinical evidence establishing biological plausibility for heparin and synthetic heparin-like drugs as therapies for COVID-19 through anti-viral and anti-inflammatory effects. Finally, we discuss known adverse effects and theoretical off-target effects that may temper enthusiasm for the adoption of heparin as a therapy in COVID-19 without confirmatory prospective randomized controlled trials. Despite previous failures of anticoagulants in critical illness, plausibility of heparin for COVID-19 is sufficiently robust to justify urgent randomized controlled trials to determine the safety and effectiveness of this therapy.

Title: Towards treatment planning of COVID-19: Rationale and hypothesis for the use of multiple immunosuppressive agents: anti-antibodies, immunoglobulins, and corticosteroids Content: Abstract The novel coronavirus, SARS-CoV2, can cause a potentially fatal disease, COVID-19, in humans. Here, we will provide an overview of therapeutic options for COVID-19. Plasma from patients recovered from COVID-19 that contains antibodies against SARS-CoV2 has shown promising results in patients with severe COVID-19. Also, IVIG, combined with moderate-dose of corticosteroids, might improve patient outcomes. Evidence links COVID-19 to variable degrees of inflammation. Studies show that the use of corticosteroids might accelerate recovery from COVID-19. There are, however, no controlled clinical trials that show whether the use of corticosteroids can reduce COVID-19-related death. Also, the pro-inflammatory cytokine IL6 is the best-documented cytokine in COVID-19 correlated with severity, criticality, viral load, and prognosis of patients with COVID-19. Tocilizumab, a monoclonal antibody against IL6, could confer clinical benefit in patients with high IL6 levels. Essential elements that process SARS-CoV2 cell entry and specific characteristics that allow SARS-CoV2 to escape the immune system have the potential as targets for COVID-19 therapy.

Title: Therapeutic potential of ciclesonide inahalation for COVID-19 pneumonia: Report of three cases Content: Abstract No specific and effective anti-viral treatment has been approved for COVID-19 so far. Systemic corticosteroid has been sometimes administered to severe infectious diseases combined with the specific treatment. However, as lack of the specific anti-SARS-CoV-2 drug, systemic steroid treatment has not been recommended for COVID-19. We report here three cases of the COVID-19 pneumonia successfully treated with ciclesonide inhalation. Rationale of the treatment is to mitigate the local inflammation with inhaled steroid that stays in the lung and to inhibit proliferation of the virus by antiviral activity. Larger and further studies are warranted to confirm the result of these cases.

Title: Pharmacotherapy in COVID-19; A narrative review for emergency providers Content: INTRODUCTION: The COVID-19 pandemic has been particularly challenging due to a lack of established therapies and treatment guidelines. With the rapid transmission of disease, even the off-label use of available therapies has been impeded by limited availability. Several antivirals, antimalarials, and biologics are being considered for treatment at this time. The purpose of this literature review is to synthesize the available information regarding treatment options for COVID-19 and serve as a resource for health care professionals. OBJECTIVES: This narrative review was conducted to summarize the effectiveness of current therapy options for COVID-19 and address the controversial use of non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). PubMed and SCOPUS were queried using a combination of the keywords "COVID 19," "SARS-CoV-2," and "treatment." All types of studies were evaluated including systematic reviews, case-studies, and clinical guidelines. DISCUSSION: There are currently no therapeutic drugs available that are directly active against SARS-CoV-2; however, several antivirals (remdesivir, favipiravir) and antimalarials (chloroquine, hydroxychloroquine) have emerged as potential therapies. Current guidelines recommend combination treatment with hydroxychloroquine/azithromycin or chloroquine, if hydroxychloroquine is unavailable, in patients with moderate disease, although these recommendations are based on limited evidence. Remdesivir and convalescent plasma may be considered in critical patients with respiratory failure; however, access to these therapies may be limited. Interleukin-6 (IL-6) antagonists may be used in patients who develop evidence of cytokine release syndrome (CRS). Corticosteroids should be avoided unless there is evidence of refractory septic shock, acute respiratory distress syndrome (ARDS), or another compelling indication for their use. ACE inhibitors and ARBs should not be discontinued at this time and ibuprofen may be used for fever. CONCLUSION: There are several ongoing clinical trials that are testing the efficacy of single and combination treatments with the drugs mentioned in this review and new agents are under development. Until the results of these trials become available, we must use the best available evidence for the prevention and treatment of COVID-19. Additionally, we can learn from the experiences of healthcare providers around the world to combat this pandemic.

Title: Corticosteroid therapy in ENT in the context of the COVID-19 pandemic Content: ABSTRACT This consensus statement about the indications and modalities of corticosteroid treatment in the context of the COVID-19 pandemic was jointly written by experts from the French Association of Otology and Oto-Neurology (AFON) and from the French Society of Otorhinolaryngology, Head and Neck Surgery (SFORL). There is currently not enough data in favour of danger or benefit from corticosteroids in COVID-19, so until this matter is resolved it is advisable to limit their indications to the most serious clinical pictures for which it is well established that this type of treatment has a positive impact on the progression of symptoms. In Grade V and VI Bell's palsy according to the House-Brackmann grading system, a week’s course of oral corticosteroids is recommended. Corticosteroid therapy is also recommended in cases of sudden hearing loss of more than 60 dB, either in the form of intratympanic injections or a week’s course of oral medication. In rhinology, there is no indication for systemic corticosteroid therapy in the current situation. However, patients are advised to continue with their local corticosteroid therapy in the form of a nasal spray or by inhalation. Treatments with corticosteroid nasal sprays can still be prescribed if there is no alternative.

Title: Towards treatment planning of COVID-19: Rationale and hypothesis for the use of multiple immunosuppressive agents: Anti-antibodies, immunoglobulins, and corticosteroids Content: The novel coronavirus, SARS-CoV2, can cause a potentially fatal disease, COVID-19, in humans. Here, we will provide an overview of therapeutic options for COVID-19. Plasma from patients recovered from COVID-19 that contains antibodies against SARS-CoV2 has shown promising results in patients with severe COVID-19. Also, IVIG, combined with moderate-dose of corticosteroids, might improve patient outcomes. Evidence links COVID-19 to variable degrees of inflammation. Studies show that the use of corticosteroids might accelerate recovery from COVID-19. There are, however, no controlled clinical trials that show whether the use of corticosteroids can reduce COVID-19-related death. Also, the pro-inflammatory cytokine IL6 is the best-documented cytokine in COVID-19 correlated with severity, criticality, viral load, and prognosis of patients with COVID-19. Tocilizumab, a monoclonal antibody against IL6, could confer clinical benefit in patients with high IL6 levels. Essential elements that process SARS-CoV2 cell entry and specific characteristics that allow SARS-CoV2 to escape the immune system have the potential as targets for COVID-19 therapy.

Title: Pharmacotherapy in COVID-19; A narrative review for emergency providers Content: INTRODUCTION: The COVID-19 pandemic has been particularly challenging due to a lack of established therapies and treatment guidelines. With the rapid transmission of disease, even the off-label use of available therapies has been impeded by limited availability. Several antivirals, antimalarials, and biologics are being considered for treatment at this time. The purpose of this literature review is to synthesize the available information regarding treatment options for COVID-19 and serve as a resource for health care professionals. OBJECTIVES: This narrative review was conducted to summarize the effectiveness of current therapy options for COVID-19 and address the controversial use of non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). PubMed and SCOPUS were queried using a combination of the keywords “COVID 19,” “SARS-CoV-2,” and “treatment.” All types of studies were evaluated including systematic reviews, case-studies, and clinical guidelines. DISCUSSION: There are currently no therapeutic drugs available that are directly active against SARS-CoV-2; however, several antivirals (remdesivir, favipiravir) and antimalarials (chloroquine, hydroxychloroquine) have emerged as potential therapies. Current guidelines recommend combination treatment with hydroxychloroquine/azithromycin or chloroquine, if hydroxychloroquine is unavailable, in patients with moderate disease, although these recommendations are based on limited evidence. Remdesivir and convalescent plasma may be considered in critical patients with respiratory failure; however, access to these therapies may be limited. Interleukin-6 (IL-6) antagonists may be used in patients who develop evidence of cytokine release syndrome (CRS). Glucocorticoids should be avoided unless there is evidence of refractory septic shock, acute respiratory distress syndrome (ARDS), or another compelling indication for their use. ACE inhibitors and ARBs should not be discontinued at this time and ibuprofen may be used for fever. CONCLUSION: There are several ongoing clinical trials that are testing the efficacy of single and combination treatments with the drugs mentioned in this review and new agents are under development. Until the results of these trials become available, we must use the best available evidence for the prevention and treatment of COVID-19. Additionally, we can learn from the experiences of healthcare providers around the world to combat this pandemic.

Title: COVID-19 and Headache Medicine: A Narrative Review of Non-Steroidal Anti-Inflammatory Drug (NSAID) and Corticosteroid Use Content: OBJECTIVE: To summarize the current literature on non-steroidal anti-inflammatory drug and corticosteroid use during the coronavirus disease 2019 (COVID-19) pandemic, recognizing that these are commonly used treatments in the field of headache medicine. BACKGROUND: The use of non-steroidal anti-inflammatory drugs and corticosteroids in patients during the COVID-19 pandemic has been a controversial topic within the medical community and international and national health organizations. Lay press and social media outlets have circulated opinions on this topic despite the fact that the evidence for or against the use of these medications is sparse. In the field of headache medicine, these medications are used commonly and both patients and clinicians may have questions or hesitations pertaining to their use during the COVID-19 pandemic. METHODS: A detailed search of the scientific and popular literature was performed. RESULTS: There is limited literature pertaining to the safety of non-steroidal anti-inflammatory drugs and corticosteroids during the COVID-19 pandemic. To date, there are no clear scientific data that preclude the use of non-steroidal anti-inflammatory drugs in the general population who may acquire COVID-19 or in those acutely infected with the virus. Several health organizations have concluded that treatment with corticosteroids during active infection should be avoided due to concerns of prolonged viral shedding in the respiratory tract and the lack of survival benefit based on the data from past coronaviruses and influenza virus; specific exceptions exist including treatment for underlying asthma or chronic obstructive pulmonary disease, septic shock, and acute respiratory distress syndrome. CONCLUSION: Scientific information regarding the COVID-19 pandemic is constantly evolving, and limited or contradictory information can lead to confusion for both patients and clinicians. It is recommended that prior to prescribing non-steroidal anti-inflammatory drugs and steroids for the treatment of headache, clinicians have open discussions with their patients about the potential risks and benefits of using these medications during the COVID-19 pandemic. This manuscript summarizes the currently available evidence and understanding about these risks and benefits to help clinicians navigate such discussions.

Title: Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review Content: Importance: The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. Observations: No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. Conclusions and Relevance: The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.

Title: Role of adjunctive treatment strategies in COVID-19 and a review of international and national clinical guidelines Content: The coronavirus disease (COVID-19) pandemic has led to a global struggle to cope with the sheer numbers of infected persons, many of whom require intensive care support or eventually succumb to the illness. The outbreak is managed by a combination of disease containment via public health measures and supportive care for those who are affected. To date, there is no specific anti-COVID-19 treatment. However, the urgency to identify treatments that could turn the tide has led to the emergence of several investigational drugs as potential candidates to improve outcome, especially in the severe to critically ill. While many of these adjunctive drugs are being investigated in clinical trials, professional bodies have attempted to clarify the setting where the use of these drugs may be considered as off-label or compassionate use. This review summarizes the clinical evidence of investigational adjunctive treatments used in COVID-19 patients as well as the recommendations of their use from guidelines issued by international and national organizations in healthcare.

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: Reducing dexamethasone antiemetic prophylaxis during the COVID-19 pandemic: recommendations from Ontario, Canada Content: PURPOSE: People with cancer face an elevated risk of infection and severe sequelae from COVID-19. Dexamethasone is commonly used for antiemetic prophylaxis with systemic therapy for cancer. However, dexamethasone is associated with increased risk of viral and respiratory infections, and causes lymphopenia, which is associated with worse outcomes during COVID-19 infections. Our purpose was to minimize dexamethasone exposure during antiemetic prophylaxis for systemic therapy for solid tumors during the COVID-19 pandemic, while maintaining control of nausea and emesis. METHODS: We convened an expert panel to systematically review the literature and formulate consensus recommendations. RESULTS: No studies considered the impact of dexamethasone-based antiemetic regimens on the risk and severity of COVID-19 infection. Expert consensus recommended modifications to the 2019 Cancer Care Ontario Antiemetic Recommendations. CONCLUSION: Clinicians should prescribe the minimally effective dose of dexamethasone for antiemetic prophylaxis. Single-day dexamethasone dosing is recommended over multi-day dosing for regimens with high emetogenic risk excluding high-dose cisplatin, preferably in combination with palonosetron, netupitant, and olanzapine. For regimens with low emetogenic risk, 5-HT(3) antagonists are recommended over dexamethasone.

Title: Reducing dexamethasone antiemetic prophylaxis during the COVID-19 pandemic: recommendations from Ontario, Canada Content: PURPOSE: People with cancer face an elevated risk of infection and severe sequelae from COVID-19. Dexamethasone is commonly used for antiemetic prophylaxis with systemic therapy for cancer. However, dexamethasone is associated with increased risk of viral and respiratory infections, and causes lymphopenia, which is associated with worse outcomes during COVID-19 infections. Our purpose was to minimize dexamethasone exposure during antiemetic prophylaxis for systemic therapy for solid tumors during the COVID-19 pandemic, while maintaining control of nausea and emesis. METHODS: We convened an expert panel to systematically review the literature and formulate consensus recommendations. RESULTS: No studies considered the impact of dexamethasone-based antiemetic regimens on the risk and severity of COVID-19 infection. Expert consensus recommended modifications to the 2019 Cancer Care Ontario Antiemetic Recommendations. CONCLUSION: Clinicians should prescribe the minimally effective dose of dexamethasone for antiemetic prophylaxis. Single-day dexamethasone dosing is recommended over multi-day dosing for regimens with high emetogenic risk excluding high-dose cisplatin, preferably in combination with palonosetron, netupitant, and olanzapine. For regimens with low emetogenic risk, 5-HT3 antagonists are recommended over dexamethasone.

Title: The COVID-19 pandemic: is our medicine still evidence-based? Content: There is no randomized controlled trial that demonstrated the efficacy of antiviral therapy against COVID-19 yet. However, physicians are prescribing different drugs to a large part of COVID-19 population in the hope they will cure them. This does not reflect the evidence-based medicine approach. What we need is more evidence-based knowledge about what routine care practices we should to apply to ameliorate symptoms of patients and fight COVID-19 pathology.

Title: COVID‐19: A review of therapeutics under investigation Content: The COVID‐19 outbreak has disrupted global health care networks and caused thousands of deaths and an international economic downturn. Multiple drugs are being used on patients with COVID‐19 based on theoretical and in vitro therapeutic targets. Several of these therapies have been studied, but many have limited evidence behind their use, and clinical trials to evaluate their efficacy are either ongoing or have not yet begun. This review summarizes the existing evidence for medications currently under investigation for treatment of COVID‐19, including remdesivir, chloroquine/hydroxychlorquine, convalescent plasma, lopinavir/ritonavir, IL‐6 inhibitors, corticosteroids, and angiotensin‐converting enzyme inhibitors.

Title: Medikamentoznoe lechenie koronavirusnoi bolezni COVID-19: sushchestvuet li dokazatel'naya baza?/ [Drug treatment of coronavirus disease COVID-19: evidence exists?] Content: The article provides a review of foreign literature for 2020 on existing methods of drug treatment of coronavirus disease COVID-19. To date, in the treatment of COVID-19 in different countries, a little more than 10 drugs are used. The largest number of studies on the testing of these drugs is carried out by scientists from China, the USA, and European countries. It should be noted that among these drugs there is not a single new drug developed specifically for the treatment of COVID-19, the recommended and used drugs have previously been used to treat, as a rule, diseases of the viral etiology, less often another pathology. These suggestions are often based on analogy, the hypothesis of their supposed effectiveness for COVID-19. It can be assumed that a brake on the development of a drug specific for coronavirus disease is a poor knowledge of the pathogenesis of virus invasion in the body's adhesives and the development of complications. The review provides detailed literature data on drugs such as hydroxychloroquine / chloroquine, lopinavir/natinavir, remdesivir, ACE inhibitors and angiotensin converting enzyme receptor blockers, tissue plasminogen activator, as well as plasma transfusion transfusions.

Title: [Drug treatment of coronavirus disease COVID-19: evidence exists?] Content: The article provides a review of foreign literature for 2020 on existing methods of drug treatment of coronavirus disease COVID-19. To date, in the treatment of COVID-19 in different countries, a little more than 10 drugs are used. The largest number of studies on the testing of these drugs is carried out by scientists from China, the USA, and European countries. It should be noted that among these drugs there is not a single new drug developed specifically for the treatment of COVID-19, the recommended and used drugs have previously been used to treat, as a rule, diseases of the viral etiology, less often another pathology. These suggestions are often based on analogy, the hypothesis of their supposed effectiveness for COVID-19. It can be assumed that a brake on the development of a drug specific for coronavirus disease is a poor knowledge of the pathogenesis of virus invasion in the body's adhesives and the development of complications. The review provides detailed literature data on drugs such as hydroxychloroquine / chloroquine, lopinavir/natinavir, remdesivir, ACE inhibitors and angiotensin converting enzyme receptor blockers, tissue plasminogen activator, as well as plasma transfusion transfusions.

Title: Potential specific therapies in COVID-19 Content: COVID-19 has grown into a global pandemic that has strained healthcare throughout the world. There is a sense of urgency in finding a cure for this deadly virus. In this study, we reviewed the empiric options used in common practice for COVID-19, based on the literature available online, with an emphasis on human experiences with these treatments on severe acute respiratory syndrome-associated coronavirus (SARS-COV-1) and other viruses. Convalescent blood products are the most promising potential treatment for use in COVID-19. The use of chloroquine or hydroxychloroquine (HCQ), remdesivir, and tocilizumab are some of the other promising potential therapies; however, they are yet to be tested in randomized clinical trials (RCTs). The use of lopinavir-ritonavir did not prove beneficial in a large RCT. The use of corticosteroids should be avoided in COVID-19 pneumonia unless used for other indications, based on the suggestion of harm in patients with SARS-COV-1 and Middle Eastern Respiratory Syndrome (MERS) infection. The reviews of this paper are available via the supplemental material section.

Title: Consensus statement. Corticosteroid therapy in ENT in the context of the COVID-19 pandemic Content: This consensus statement about the indications and modalities of corticosteroid treatment in the context of the COVID-19 pandemic was jointly written by experts from the French Association of Otology and Oto-Neurology (AFON) and from the French Society of Otorhinolaryngology, Head and Neck Surgery (SFORL). There is currently not enough data in favour of danger or benefit from corticosteroids in COVID-19, so until this matter is resolved it is advisable to limit their indications to the most serious clinical pictures for which it is well established that this type of treatment has a positive impact on the progression of symptoms. In Grade V and VI Bell's palsy according to the House-Brackmann grading system, a week's course of oral corticosteroids is recommended. Corticosteroid therapy is also recommended in cases of sudden hearing loss of more than 60dB, either in the form of intratympanic injections or a week's course of oral medication. In rhinology, there is no indication for systemic corticosteroid therapy in the current situation. However, patients are advised to continue with their local corticosteroid therapy in the form of a nasal spray or by inhalation. Treatments with corticosteroid nasal sprays can still be prescribed if there is no alternative. Finally, systemic or local corticosteroid therapy is not indicated for bacterial ENT infections.

Title: Pharmacological development of the potential adjuvant therapeutic agents against coronavirus disease 2019 Content: As the coronavirus disease 2019 (COVID-19, also called severe acute respiratory syndrome coronavirus-2, SARSCoV-2) outbreak accelerates, vigorous and diverse efforts were made in developing treatment strategies. In addition to direct acting agents, increasing evidence showed some potential adjuvant therapies with promising efficacy against COVID-19. These therapies include immunomodulators (i.e. intravenous immunoglobulin, thymosin α-1, IL-6, tocilizumab, cyclosporine, thalidomide, fingolimod), Chinese medicines (i.e. glycyrrhizin, baicalin, Xuebijing), anti-vascular endothelial growth factors (bevacizumab), estrogen modulating drugs, statins and nutritional supplements (i.e. vitamin A, B, C, D, E and zinc). This article reviewed the pharmacological development of potential adjuvants for COVID-19 treatment.

Title: Novel Stem Cells and Nucleic Acid-Based Vaccine Trials Against Viral Outbreak: A Systematic Evaluation During COVID-2019 Pandemic Content: The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak, the cause of coronavirus disease (COVID-19), has influenced health globally. So far, there are no established management options and prophylaxis for those who have been exposed to SARS-CoV-2, and those who develop COVID-19. Documented scientific evidences in similar viral outbreaks in past suggested few therapy regimens. These rather have not shown promising results in management of current pandemic. So, in the current review, we are exploring novel treatment strategies and therapies that are being explored and are in clinical and preclinical stages of research. To explore more about the same, we directed our search towards stem cell based, DNA based, or RNA based vaccines against COVID-19 under development by various universities, institutes or pharmaceutical companies. The current scientific literature and database search were performed by exploring various Trials registry (NIH: https://clinicaltrials.gov/ and https://www.coronavirus.gov) and Chinese clinical trial registry http://www.chictr.org.cn/) and for preclinical trials various University, Institutions, Pharmaceutical companies websites and news bulletins along with google search were checked routinely from 3rd March 2020 to 16 May 2020. The term “Stem Cell therapy and COVID-19”, “Mesenchymal stem cell and corona 2019 virus”, “DNA Vaccines and COVID-19, RNA Vaccines and COVID-19” and “Cell-based therapy with SARS-CoV-2, University/Institutions and COVID-19 research” were used. The vaccine trials (Stem Cells/DNA/RNA) which were cancelled were not included in this review. Similarly, few others like repurposing of drugs, Nano Vaccines, other miscellaneous trials of Herbs, Music therapy etc., were also excluded. In the present review, we have included the various novel therapies like stem cell therapy, DNA or RNA vaccines which are under development and if proven successful may have a lasting impact on the health industry.

Title: Efficacy and safety of corticosteroids in COVID-19 based on evidence for COVID-19, other coronavirus infections, influenza, community-acquired pneumonia and acute respiratory distress syndrome: a systematic review and meta-analysis Content: BACKGROUND: Very little direct evidence exists on use of corticosteroids in patients with coronavirus disease 2019 (COVID-19). Indirect evidence from related conditions must therefore inform inferences regarding benefits and harms. To support a guideline for managing COVID-19, we conducted systematic reviews examining the impact of corticosteroids in COVID-19 and related severe acute respiratory illnesses. METHODS: We searched standard international and Chinese biomedical literature databases and prepublication sources for randomized controlled trials (RCTs) and observational studies comparing corticosteroids versus no corticosteroids in patients with COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). For acute respiratory distress syndrome (ARDS), influenza and community-acquired pneumonia (CAP), we updated the most recent rigorous systematic review. We conducted random-effects meta-analyses to pool relative risks and then used baseline risk in patients with COVID-19 to generate absolute effects. RESULTS: In ARDS, according to 1 small cohort study in patients with COVID-19 and 7 RCTs in non-COVID-19 populations (risk ratio [RR] 0.72, 95% confidence interval [CI] 0.55 to 0.93, mean difference 17.3% fewer; low-quality evidence), corticosteroids may reduce mortality. In patients with severe COVID-19 but without ARDS, direct evidence from 2 observational studies provided very low-quality evidence of an increase in mortality with corticosteroids (hazard ratio [HR] 2.30, 95% CI 1.00 to 5.29, mean difference 11.9% more), as did observational data from influenza studies. Observational data from SARS and MERS studies provided very low-quality evidence of a small or no reduction in mortality. Randomized controlled trials in CAP suggest that corticosteroids may reduce mortality (RR 0.70, 95% CI 0.50 to 0.98, 3.1% lower; very low-quality evidence), and may increase hyperglycemia. INTERPRETATION: Corticosteroids may reduce mortality for patients with COVID-19 and ARDS. For patients with severe COVID-19 but without ARDS, evidence regarding benefit from different bodies of evidence is inconsistent and of very low quality.

Title: Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of anti-infective therapy (SITA) and the Italian Society of Pulmonology (SIP) Content: Abstract Background SARS-CoV-2 is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries. The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure. At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries. Objectives To narratively summarize the available literature on the management of COVID-19, in the attempt to combine current evidence and frontline opinions and provide balanced answers to pressing clinical questions. Sources Inductive PubMed search for publications relevant to the topic. Content The available literature and the authors’ frontline-based opinion are summarized in brief narrative answers to selected clinical questions, plus a conclusive statement for each answer. Implications Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19. Physicians must be aware that, being not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled in randomized clinical trials (RCT). Access to well-designed RCT should be expanded as much as possible, being the most secure way to change for the better our approach to COVID-19 patients.

Title: Efficacy and safety of corticosteroids in COVID-19 based on evidence for COVID-19, other coronavirus infections, influenza, community-acquired pneumonia and acute respiratory distress syndrome: a systematic review and meta-analysis. Content: BACKGROUND Very little direct evidence exists on use of corticosteroids in patients with coronavirus disease 2019 (COVID-19). Indirect evidence from related conditions must therefore inform inferences regarding benefits and harms. To support a guideline for managing COVID-19, we conducted systematic reviews examining the impact of corticosteroids in COVID-19 and related severe acute respiratory illnesses. METHODS We searched standard international and Chinese biomedical literature databases and prepublication sources for randomized controlled trials (RCTs) and observational studies comparing corticosteroids versus no corticosteroids in patients with COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). For acute respiratory distress syndrome (ARDS), influenza and community-acquired pneumonia (CAP), we updated the most recent rigorous systematic review. We conducted random-effects meta-analyses to pool relative risks and then used baseline risk in patients with COVID-19 to generate absolute effects. RESULTS In ARDS, according to 1 small cohort study in patients with COVID-19 and 7 RCTs in non-COVID-19 populations (risk ratio [RR] 0.72, 95% confidence interval [CI] 0.55 to 0.93, mean difference 17.3% fewer; low-quality evidence), corticosteroids may reduce mortality. In patients with severe COVID-19 but without ARDS, direct evidence from 2 observational studies provided very low-quality evidence of an increase in mortality with corticosteroids (hazard ratio [HR] 2.30, 95% CI 1.00 to 5.29, mean difference 11.9% more), as did observational data from influenza studies. Observational data from SARS and MERS studies provided very low-quality evidence of a small or no reduction in mortality. Randomized controlled trials in CAP suggest that corticosteroids may reduce mortality (RR 0.70, 95% CI 0.50 to 0.98, 3.1% lower; very low-quality evidence), and may increase hyperglycemia. INTERPRETATION Corticosteroids may reduce mortality for patients with COVID-19 and ARDS. For patients with severe COVID-19 but without ARDS, evidence regarding benefit from different bodies of evidence is inconsistent and of very low quality.

Title: Current Status of the COVID-19 Outbreak and Emerging Management through Pharmaceutical Therapeutic Strategy. Content: The latest SARS COV2 coronavirus contributes to a pandemic of millions of COVID-19. Because there is no defensive immunity in humans and a virus can overcome inborn immune reaction, it can propagate unhindered, mostly in tissues contaminated. No unique therapies for COVID-19 contaminated patients are available at this time. The insights learned from previous respiratory viral infection control have given guidance into COVID-19 therapy. Several complementary treatments have been tentatively introduced in hospital environments such as immune-modulators, antiviral, convalescent plasma transfusions and natural products. In COVID-19 patients, some of these therapies have provided substantial curative benefits. Moreover, numerous studies and clinical trials are being carried out in order to determine the efficacy of current pharmaceutical and natural products and establish possible therapeutic strategies for producing novel COVID-19 medicines. We summarized and defined the modes of mechanism, protection and efficacy on existing therapeutic strategies for diseases linked to COVID-19 infection.

Title: Rethinking the role of hydroxychloroquine in the treatment of COVID-19 Content: There are currently no proven or approved treatments for coronavirus disease 2019 (COVID-19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID-19 are treated with these agents and more evidence accumulates, there continues to be no high-quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto-immune conditions, and provided a component in the original rationale for their use in patients with COVID-19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID-19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID-19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID-19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case-by-case basis after rigorous consideration of the risks and benefits of this therapeutic approach.

Title: Update for Anaesthetists on Clinical Features of COVID-19 Patients and Relevant Management Content: When preparing for the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the coronavirus infection disease (COVID-19) questions arose regarding various aspects concerning the anaesthetist. When reviewing the literature it became obvious that keeping up-to-date with all relevant publications is almost impossible. We searched for and summarised clinically relevant topics that could help making clinical decisions. This is a subjective analysis of literature concerning specific topics raised in our daily practice (e.g., clinical features of COVID-19 patients; ventilation of the critically ill COVID-19 patient; diagnostic of infection with SARS-CoV-2; stability of the virus; Covid-19 in specific patient populations, e.g., paediatrics, immunosuppressed patients, patients with hypertension, diabetes mellitus, kidney or liver disease; co-medication with non-steroidal anti-inflammatory drugs (NSAIDs); antiviral treatment) and we believe that these answers help colleagues in clinical decision-making. With ongoing treatment of severely ill COVID-19 patients other questions will come up. While respective guidelines on these topics will serve clinicians in clinical practice, regularly updating all guidelines concerning COVID-19 will be a necessary, although challenging task in the upcoming weeks and months. All recommendations during the current extremely rapid development of knowledge must be evaluated on a daily basis, as suggestions made today may be out-dated with the new evidence available tomorrow.

Title: Etoposid-based therapy for severe forms of COVID-19 Content: Abstract The new coronavirus infection COVID-19 has quickly become a global health emergency. Mortality is principally due to severe Acute Respiratory Distress Syndrome (ARDS) which relays only on supportive treatment. Numerous pathological, clinical and laboratory findings rise the similarity between moderate to severe COVID-19 and haemophagocytic lymphohistiocytosis (HLH). Etoposide-based protocol including dexametasone is the standard of care for secondary HLH. The protocol has been successfully used in HLHs that are secondary to EBV and H1N1 infections by inducing complete response and pronged survival. These observations prompt to consider this cytotoxic therapy in HLH associated to moderately severe to severe forms of COVID-19.

Title: Pharmacological development of the potential adjuvant therapeutic agents against coronavirus disease 2019. Content: As the coronavirus disease 2019 (COVID-19, also called severe acute respiratory syndrome coronavirus-2, SARSCoV-2) outbreak accelerates, vigorous and diverse efforts were made in developing treatment strategies. In addition to direct acting agents, increasing evidence showed some potential adjuvant therapies with promising efficacy against COVID-19. These therapies include immunomodulators (i.e. intravenous immunoglobulin, thymosin α-1, IL-6, tocilizumab, cyclosporine, thalidomide, fingolimod), Chinese medicines (i.e. glycyrrhizin, baicalin, Xuebijing), anti-vascular endothelial growth factors (bevacizumab), estrogen modulating drugs, statins and nutritional supplements (i.e. vitamin A, B, C, D, E and zinc). This article reviewed the pharmacological development of potential adjuvants for COVID-19 treatment.

Title: Comparative Efficacy and Safety of Pharmacological Managements for Hospitalized COVID-19 Patients: Protocol for Systematic Review and Trade-Off Network Meta-Analysis. Content: Coronavirus-Disease 2019 (COVID-19) is the clinical disease caused by the SARS-CoV-2 virus, the infectious agent causing the ongoing pandemic that has impacted the lives of hundreds of millions of people in almost every nation worldwide. It is a potentially fatal disease to many vulnerable patients including the elderly and those with chronic illnesses; but because this virus is a novel one, there are no firmly established treatment protocols. Many treatment methods are being investigated worldwide, and scientific conclusions drawn from these endeavors are crucial for healthcare professionals in combating this disease. In this network meta-analysis, we focus specifically on the pharmacologic agents that have been investigated for the treatment of COVID-19 and aim to produce a comprehensive picture of the evidence from current data in order to produce relevant insights on the comparative efficacy and safety profiles of various pharmacologic agents against COVID-19.

Title: Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP) Content: BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries. The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure. At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries. OBJECTIVES: To narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and frontline opinions and to provide balanced answers to pressing clinical questions. SOURCES: Inductive PubMed search for publications relevant to the topic. CONTENT: The available literature and the authors' frontline-based opinion are summarized in brief narrative answers to selected clinical questions, with a conclusive statement provided for each answer. IMPLICATIONS: Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19. Physicians must be aware that, as they are not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled onto randomized clinical trials. Access to well-designed randomized controlled trials should be expanded as much as possible because it is the most secure way to change for the better our approach to COVID-19 patients.

Title: Rethinking the role of hydroxychloroquine in the treatment of COVID‐19 Content: There are currently no proven or approved treatments for coronavirus disease 2019 (COVID‐19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID‐19 are treated with these agents and more evidence accumulates, there continues to be no high‐quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto‐immune conditions, and provided a component in the original rationale for their use in patients with COVID‐19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID‐19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID‐19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID‐19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case‐by‐case basis after rigorous consideration of the risks and benefits of this therapeutic approach.

Title: COVID-19 and Headache Medicine: A Narrative Review of Non-Steroidal Anti-Inflammatory Drug (NSAID) and Corticosteroid Use. Content: OBJECTIVE To summarize the current literature on non-steroidal anti-inflammatory drug and corticosteroid use during the coronavirus disease 2019 (COVID-19) pandemic, recognizing that these are commonly used treatments in the field of headache medicine. BACKGROUND The use of non-steroidal anti-inflammatory drugs and corticosteroids in patients during the COVID-19 pandemic has been a controversial topic within the medical community and international and national health organizations. Lay press and social media outlets have circulated opinions on this topic despite the fact that the evidence for or against the use of these medications is sparse. In the field of headache medicine, these medications are used commonly and both patients and clinicians may have questions or hesitations pertaining to their use during the COVID-19 pandemic. METHODS A detailed search of the scientific and popular literature was performed. RESULTS There is limited literature pertaining to the safety of non-steroidal anti-inflammatory drugs and corticosteroids during the COVID-19 pandemic. To date, there are no clear scientific data that preclude the use of non-steroidal anti-inflammatory drugs in the general population who may acquire COVID-19 or in those acutely infected with the virus. Several health organizations have concluded that treatment with corticosteroids during active infection should be avoided due to concerns of prolonged viral shedding in the respiratory tract and the lack of survival benefit based on the data from past coronaviruses and influenza virus; specific exceptions exist including treatment for underlying asthma or chronic obstructive pulmonary disease, septic shock, and acute respiratory distress syndrome. CONCLUSION Scientific information regarding the COVID-19 pandemic is constantly evolving, and limited or contradictory information can lead to confusion for both patients and clinicians. It is recommended that prior to prescribing non-steroidal anti-inflammatory drugs and steroids for the treatment of headache, clinicians have open discussions with their patients about the potential risks and benefits of using these medications during the COVID-19 pandemic. This manuscript summarizes the currently available evidence and understanding about these risks and benefits to help clinicians navigate such discussions.

Title: Mesenchymal Stem Cell Therapy for COVID-19: Present or Future Content: "COVID-19" is the word that certainly isn't forgotten by everybody who lives in the first half of the twenty-first century. COVID-19, as a pandemic, has led many researchers from different biomedical fields to find solutions or treatments to manage the pandemic. However, no standard treatment for this disease has been discovered to date. Probably, preventing the severe acute respiratory infection form of COVID-19 as the most dangerous phase of this disease can be helpful for the treatment and reduction of the death rate. In this regard, mesenchymal stem cells (MSCs)-based immunomodulation treatment has been proposed as a suitable therapeutic approach and several clinical trials have begun. Recently, MSCs according to their immunomodulatory and regenerative properties attract attention in clinical trials. After the intravenous transplantation of MSCs, a significant population of cells accumulates in the lung, which they alongside immunomodulatory effect could protect alveolar epithelial cells, reclaim the pulmonary microenvironment, prevent pulmonary fibrosis, and cure lung dysfunction. Given the uncertainties in this area, we reviewed reported clinical trials and hypotheses to provide useful information to researchers and those interested in stem cell therapy. In this study, we considered this new approach to improve patient's immunological responses to COVID-19 using MSCs and discussed the aspects of this proposed treatment. However, currently, there are no approved MSC-based approaches for the prevention and/or treatment of COVID-19 patients but clinical trials ongoing.

Title: Vademecum for the treatment of people with COVID-19. Edition 2.0, 13 March 2020 Content: The spread of COVID-19 epidemic in Italy, and particularly in Lombardy determined the need to standardize the therapeutic approach in order to offer the same indications for all hospitals in Lombardy. However, no specific drug has been previously approved for the COVID-19 treatment. The Lombardy Section of the Italian Society of Infectious and Tropical Diseases provided this «vademecum¼ with the aim to explore the current evidence about the drugs likely to be efficacious in the treatment of COVID-19. Moreover, a multidisciplinary group including critical care specialists has been created in order to provide indications about supporting measures and the use of steroids. A new grading scale has been proposed to help patients' stratification according to the severity of the respiratory conditions. Lastly, a collaborating group with immunologists and rheumatologists has been built with the aim of providing some guidance about the use of tocilizumab, a promising option for the treatment of the hyperinflammatory state occurring in most patients affected by COVID-19.

Title: Current evidence for directed and supportive investigational therapies against COVID-19 Content: Coronavirus disease 2019 (COVID-19) is a global health crisis. There is currently a great need for effective and safe therapies directed at the disease, but no drugs are presently registered for use in COVID-19. Several directed therapies have been proposed, and most are still in clinical trials. Currently available published, peer-reviewed results mostly involve small sample sizes with study limitations restricting the interpretation of the findings. Many trials currently published also do not have a control group, limiting the interpretation of the effect of the intervention. Investigational directed therapies as well as investigational supportive therapies against COVID-19 are reviewed here. Chloroquine and hydroxychloroquine show promise as directed therapies, but current trial results are conflicting. Lopinavir/ritonavir also shows potential, but was started late in the disease course in most trials. No randomised controlled evidence is currently available for remdesivir and favipiravir. Corticosteroid use is not recommended for directed therapy against COVID-19, and the role of tocilizumab is currently unclear, based on limited evidence. Early initiation of investigational directed therapies may provide benefit in selected patients. The results from larger randomised controlled trials will clarify the place of these therapies in COVID-19 treatment.

Title: Evidence based management guideline for the COVID-19 pandemic - Review article Content: COVID-19 has now been declared a pandemic. To date, COVID-19 has affected over 2.5 million people worldwide, resulting in over 170,000 reported deaths. Numerous preventative strategies and non-pharmaceutical interventions have been employed to mitigate the spread of disease including careful infection control, the isolation of patients, and social distancing. Management is predominantly focused on the provision of supportive care, with oxygen therapy representing the major treatment intervention. Medical therapy involving corticosteroids and antivirals have also been encouraged as part of critical management schemes. However, there is at present no specific antiviral recommended for the treatment of COVID-19, and no vaccine is currently available. Despite the strategic implementation of these measures, the number of new reported cases continues to rise at a profoundly alarming rate. As new findings emerge, there is an urgent need for up-to-date management guidelines. In response to this call, we review what is currently known regarding the management of COVID-19, and offer an evidence-based review of current practice.

Title: Natural History of COVID-19 and Current Knowledge on Treatment Therapeutic Options Content: Despite intense research there is currently no effective vaccine available against the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in the later 2019 and responsible for the COVID-19 pandemic. This infectious and communicable disease has become one of the major public health challenges in the world. The clinical management of COVID-19 has been limited to infection prevention and control measures associated with supportive care such as supplemental oxygen and mechanical ventilation. Meanwhile efforts to find an effective treatment to inhibit virus replication, mitigate the symptoms, increase survival and decrease mortality rate are ongoing. Several classes of drugs, many of them already in use for other diseases, are being evaluated based on the body of clinical knowledge obtained from infected patients regarding to the natural history and evolution of the infection. Herein we will provide an updated overview of the natural history and current knowledge on drugs and therapeutic agents being tested for the prevention and treatment of COVID-19. These include different classes of drugs such as antiviral agents (chloroquine, ivermectin, nitazoxanide, hydroxychloroquine, lopinavir, remdesivir, tocilizumab), supporting agents (Vitamin C, Vitamin D, azithromycin, corticosteroids) and promising investigational vaccines. Considering the controversies and excessive number of compounds being tested and reported in the literature we hope that this review can provide useful and updated consolidated information on potential drugs used to prevent, control and treat COVID-19 patients worldwide.

Title: Thalidomide-Revisited: Are COVID-19 Patients Going to Be the Latest Victims of Yet Another Theoretical Drug-Repurposing? Content: The coronavirus disease 2019 (COVID-19) pandemic is a worldwide threatening health issue. The progression of this viral infection occurs in the airways of the lungs with an exaggerated inflammatory response referred to as the "cytokine storm" that can lead to lethal lung injuries. In the absence of an effective anti-viral molecule and until the formulation of a successful vaccine, anti-inflammatory drugs might offer a complementary tool for controlling the associated complications of COVID-19 and thus decreasing the subsequent fatalities. Drug repurposing for several molecules has emerged as a rapid temporary solution for COVID-19. Among these drugs is Thalidomide; a historically emblematic controversial molecule that harbors an FDA approval for treating erythema nodosum leprosum (ENL) and multiple myeloma (MM). Based on just one-case report that presented positive outcomes in a patient treated amongst others with Thalidomide, two clinical trials on the efficacy and safety of Thalidomide in treating severe respiratory complications in COVID-19 patients were registered. Yet, the absence of substantial evidence on Thalidomide usage in that context along with the discontinued studies on the efficiency of this drug in similar pulmonary diseases, might cause a significant obstacle for carrying out further clinical evaluations. Herein, we will discuss the theoretical effectiveness of Thalidomide in attenuating inflammatory complications that are encountered in COVID-19 patients while pinpointing the lack of the needed evidences to move forward with this drug.

Title: Mesenchymal Stem Cell Therapy for COVID-19: Present or Future Content: “COVID-19” is the word that certainly isn’t forgotten by everybody who lives in the first half of the twenty-first century. COVID-19, as a pandemic, has led many researchers from different biomedical fields to find solutions or treatments to manage the pandemic. However, no standard treatment for this disease has been discovered to date. Probably, preventing the severe acute respiratory infection form of COVID-19 as the most dangerous phase of this disease can be helpful for the treatment and reduction of the death rate. In this regard, mesenchymal stem cells (MSCs)-based immunomodulation treatment has been proposed as a suitable therapeutic approach and several clinical trials have begun. Recently, MSCs according to their immunomodulatory and regenerative properties attract attention in clinical trials. After the intravenous transplantation of MSCs, a significant population of cells accumulates in the lung, which they alongside immunomodulatory effect could protect alveolar epithelial cells, reclaim the pulmonary microenvironment, prevent pulmonary fibrosis, and cure lung dysfunction. Given the uncertainties in this area, we reviewed reported clinical trials and hypotheses to provide useful information to researchers and those interested in stem cell therapy. In this study, we considered this new approach to improve patient’s immunological responses to COVID-19 using MSCs and discussed the aspects of this proposed treatment. However, currently, there are no approved MSC-based approaches for the prevention and/or treatment of COVID-19 patients but clinical trials ongoing.

Title: Systemic autoimmune diseases, anti-rheumatic therapies, COVID-19 infection risk and patient outcomes Content: As of June 10th 2020 about 7.2 million individuals have tested positive for, and more than 410,000 have died due to COVID-19. In this review we outline the pathophysiology that underpins the potential use of anti-rheumatic therapies for severe COVID-19 infection and summarize the current evidence regarding the risk and outcome of COVID-19 in patients with systemic autoimmune diseases. Thus far there is no convincing evidence that any disease-modifying anti-rheumatic drug (conventional synthetic, biologic or targeted synthetic) including hydroxychloroquine, may protect against severe COVID-19 infection; answers about their possible usefulness in the management of the cytokine storm associated with severe COVID-9 infection will only arise from ongoing randomized controlled trials. Evidence on COVID-19 risk and outcome in patients with systemic autoimmune diseases is extremely limited; thus, any conclusions would be unsafe and should be seen with great caution. At present, the risk and severity (hospitalization, intensive care unit admission and death) of COVID-19 infection in people with autoimmune diseases do not appear particularly dissimilar to the general population, with the possible exception of hospitalization in patients exposed to high glucocorticoid doses. At this stage it is impossible to draw any conclusions for differences in COVID-19 risk and outcome between different autoimmune diseases and between the various immunomodulatory therapies used for them. More research in the field is obviously required, including as a minimum careful and systematic epidemiology and appropriately controlled clinical trials.

Title: Associations between immune-suppressive and stimulating drugs and novel COVID-19—a systematic review of current evidence Content: BACKGROUND: Cancer and transplant patients with COVID-19 have a higher risk of developing severe and even fatal respiratory diseases, especially as they may be treated with immune-suppressive or immune-stimulating drugs. This review focuses on the effects of these drugs on host immunity against COVID-19. METHODS: Using Ovid MEDLINE, we reviewed current evidence for immune-suppressing or -stimulating drugs: cytotoxic chemotherapy, low-dose steroids, tumour necrosis factorα (TNFα) blockers, interlukin-6 (IL-6) blockade, Janus kinase (JAK) inhibitors, IL-1 blockade, mycophenolate, tacrolimus, anti-CD20 and CTLA4-Ig. RESULTS: 89 studies were included. Cytotoxic chemotherapy has been shown to be a specific inhibitor for severe acute respiratory syndrome coronavirus in in vitro studies, but no specific studies exist as of yet for COVID-19. No conclusive evidence for or against the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of COVID-19 patients is available, nor is there evidence indicating that TNFα blockade is harmful to patients in the context of COVID-19. COVID-19 has been observed to induce a pro-inflammatory cytokine generation and secretion of cytokines, such as IL-6, but there is no evidence of the beneficial impact of IL-6 inhibitors on the modulation of COVID-19. Although there are potential targets in the JAK-STAT pathway that can be manipulated in treatment for coronaviruses and it is evident that IL-1 is elevated in patients with a coronavirus, there is currently no evidence for a role of these drugs in treatment of COVID-19. CONCLUSION: The COVID-19 pandemic has led to challenging decision-making about treatment of critically unwell patients. Low-dose prednisolone and tacrolimus may have beneficial impacts on COVID-19. The mycophenolate mofetil picture is less clear, with conflicting data from pre-clinical studies. There is no definitive evidence that specific cytotoxic drugs, low-dose methotrexate for auto-immune disease, NSAIDs, JAK kinase inhibitors or anti-TNFα agents are contraindicated. There is clear evidence that IL-6 peak levels are associated with severity of pulmonary complications.

Title: Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. Content: Importance The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. Observations No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. Conclusions and Relevance The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.

Title: Vademecum for the treatment of people with COVID-19. Edition 2.0, 13 March 2020. Content: The spread of COVID-19 epidemic in Italy, and particularly in Lombardy determined the need to standardize the therapeutic approach in order to offer the same indications for all hospitals in Lombardy. However, no specific drug has been previously approved for the COVID-19 treatment. The Lombardy Section of the Italian Society of Infectious and Tropical Diseases provided this «vademecum» with the aim to explore the current evidence about the drugs likely to be efficacious in the treatment of COVID-19. Moreover, a multidisciplinary group including critical care specialists has been created in order to provide indications about supporting measures and the use of steroids. A new grading scale has been proposed to help patients' stratification according to the severity of the respiratory conditions. Lastly, a collaborating group with immunologists and rheumatologists has been built with the aim of providing some guidance about the use of tocilizumab, a promising option for the treatment of the hyperinflammatory state occurring in most patients affected by COVID-19.

Title: Can cell therapies halt cytokine storm in severe COVID-19 patients? Content: A pilot study of COVID-19 patients treated with mesenchymal stem cells demonstrates safety. Mesenchymal stromal cell (MSC) therapies, which have been explored for decades as a treatment for inflammatory diseases, are now being called into action to combat the cytokine storm induced by COVID-19. The severity of COVID-19 may be due in part to the patient's response to the infection. In some patients, the virus induces an outpouring of inflammatory mediators that leads to swelling, inflammatory infiltration, and reduced gas exchange in the alveoli of the lungs. To combat this cytokine storm, over 20 clinical trials aiming to treat COVID-19 with MSCs have been registered with ClinicalTrials.gov. Leng et al. recently conducted a pilot study of MSC transplantation in 10 patients in China. All patients tested positive for SARS-CoV-2 by polymerase chain reaction and had fever, shortness of breath, cough, and oxygen saturation at rest <95%. Seven of the patients received intravenous infusions of allogeneic MSCs while three received saline as a placebo control. All seven MSC treated patients experienced resolution of symptoms while one of the placebo-treated patients went on to develop ARDS and another died. The response of the most severely ill patient treated with MSCs was monitored throughout recovery. Of note, C-reactive protein levels dropped 10-fold after MSC treatment, suggesting a drop in systemic inflammation. Analysis of cytokine levels before and after treatment revealed that MSC treatment, but not placebo, was associated with a halt in the increase of serum tumor necrosis factor–α and an increase in anti-inflammatory interleukin-10 concentrations in the serum. Although this study is not designed to make definitive claims regarding the efficacy of MSC therapy for COVID-19 or the mechanisms by which MSCs may function to prevent or treat cytokine storm, it does provide important safety data and hints of efficacy that have motivated further exploration of MSCs as a treatment for COVID-19. Of particular note is a randomized, multicenter, placebo-controlled, Phase 2/3 trial enrolling 240 patients being conducted through a public-private partnership between the U.S. National Institutes of Health–funded Cardiothoracic Surgical Trials Network and Mesoblast. As multiple clinical trials are launched around the world, we should not have to wait long to determine if MSCs are a viable and effective treatment option for severe COVID-19.

Title: Thalidomide-Revisited: Are COVID-19 Patients Going to Be the Latest Victims of Yet Another Theoretical Drug-Repurposing? Content: The coronavirus disease 2019 (COVID-19) pandemic is a worldwide threatening health issue. The progression of this viral infection occurs in the airways of the lungs with an exaggerated inflammatory response referred to as the “cytokine storm” that can lead to lethal lung injuries. In the absence of an effective anti-viral molecule and until the formulation of a successful vaccine, anti-inflammatory drugs might offer a complementary tool for controlling the associated complications of COVID-19 and thus decreasing the subsequent fatalities. Drug repurposing for several molecules has emerged as a rapid temporary solution for COVID-19. Among these drugs is Thalidomide; a historically emblematic controversial molecule that harbors an FDA approval for treating erythema nodosum leprosum (ENL) and multiple myeloma (MM). Based on just one-case report that presented positive outcomes in a patient treated amongst others with Thalidomide, two clinical trials on the efficacy and safety of Thalidomide in treating severe respiratory complications in COVID-19 patients were registered. Yet, the absence of substantial evidence on Thalidomide usage in that context along with the discontinued studies on the efficiency of this drug in similar pulmonary diseases, might cause a significant obstacle for carrying out further clinical evaluations. Herein, we will discuss the theoretical effectiveness of Thalidomide in attenuating inflammatory complications that are encountered in COVID-19 patients while pinpointing the lack of the needed evidences to move forward with this drug.

Title: Treatment Considerations for COVID-19: A Critical Review of the Evidence (or Lack Thereof) Content: Abstract The novel severe acute respiratory syndrome coronavirus 2 is causing a worldwide pandemic that may lead to a highly morbid and potentially fatal coronavirus disease-19 (COVID-19). There is currently no drug that has been proven as an effective therapy for COVID-19. Several candidate drugs are being considered and evaluated for treatment. This includes clinically-available drugs, such as chloroquine, hydroxychloroquine, and lopinavir/ritonavir, which are being repurposed for the treatment of COVID-19. Novel experimental therapies, such as remdesivir and favipiravir, are also actively being investigated for antiviral efficacy. Clinically-available and investigational immunomodulators, such as the IL-6 inhibitors tocilizumab and sarilumab and the anti-GMCSF lenzilumab, are being tested for their anticipated effect in counteracting the pro-inflammatory cytokine environment that characterizes severe and critical COVID-19. This review article examines the evidence behind the potential use of these leading drug candidates for the treatment of COVID-19. The authors conclude, based on this review, that there is still no high-quality evidence to support any of these proposed drug therapies. The authors, therefore, encourage the enrollment of eligible patients to multiple ongoing clinical trials that assess the efficacy and safety of these candidate therapies. Until the results of controlled trials are available, none of the suggested therapeutics is clinically proven as an effective therapy for COVID-19.

Title: COVID-19 Treatment: Close to a Cure? – A Rapid Review of Pharmacotherapies for the Novel Coronavirus Content: Currently, there is no approved therapy for COVID-19. The World Health Organization therefore endorse supportive care only. However, frontline clinicians and researchers have been experimenting with several virus-based and host-based therapeutics since the outbreak in China. China's National Health Commission has issued the first COVID-19 Treatment Guideline with therapy suggestions (7(th) edition attached) which inspired following clinical studies worldwide. Major therapeutics are evaluated in this review. Key evidence from in vitro researches, animal models and clinical researches in emerging coronaviruses are examined. Antiviral therapies remdesivir, lopinavir/ritonavir and umifenovir, if considered, could be initiated before the peak of viral replication for optimal outcomes. Ribavirin may be beneficial as an add-on therapy and is ineffective as a monotherapy. Corticosteroids use should be limited to indicating comorbidities. IVIG is not recommended due to lack of data in COVID-19. Xuebijing may benefit patients with complications of bacterial pneumonia or sepsis. The efficacy of interferon is unclear due to conflicting outcomes in coronavirus studies. Chloroquine and hydroxychloroquine have shown in vitro inhibition of SARS-CoV-2, and the studies on clinical efficacy and whether the benefits outweigh the risk of dysrhythmias remain inconclusive. For patients who developed cytokine release syndrome, interleukin-6 inhibitors may be beneficial.

Title: Review of Emerging Pharmacotherapy for the Treatment of Coronavirus Disease 2019 Content: The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID-19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacologic management of patients with COVID-19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immunomodulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS-CoV-2. Critically ill patients with COVID-19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID-19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.

Title: Evidence Based Management Guideline for the COVID-19 Pandemic - Review article Content: ABSTRACT COVID-19 has now been declared a pandemic. To date, COVID-19 has affected over 944,181 people worldwide, resulting in over 47,312 reported deaths. Numerous preventative strategies and non-pharmaceutical interventions have been employed to mitigate the spread of disease including careful infection control, the isolation of patients, and social distancing. Management is predominantly focused on the provision of supportive care, with oxygen therapy representing the major treatment intervention. Medical therapy involving corticosteroids and antivirals have also been encouraged as part of critical management schemes. However, there is at present no specific antiviral recommended for the treatment of COVID-19, and no vaccine is currently available. Despite the strategic implementation of these measures, the number of new reported cases continues to rise at a profoundly alarming rate. As new findings emerge, there is an urgent need for up-to-date management guidelines. In response to this call, we review what is currently known regarding the management of COVID-19, and offer an evidence-based review of current practice.

Title: Outpatient treatment of COVID-19 with steroids in the phase of mild pneumonia without the need for admission as an opportunity to modify the course of the disease: A structured summary of a randomised controlled trial Content: OBJECTIVES: The aim of this study is to explore the effectiveness and safety of oral corticosteroids (prednisone) in the treatment of early stage SARS-Cov-2 pneumonia in patients who do not yet meet hospital admission criteria. TRIAL DESIGN: Randomized clinical trial, controlled, open, parallel group, to evaluate the effectiveness of steroids in adult patients with confirmed COVID-19, with incipient pulmonary involvement, without hospital admission criteria. Patients will be stratified by the presence or not of radiological data on pneumonia. PARTICIPANTS: We will include patients with early stage SARS-Cov-2 pneumonia who do not meet hospital admission criteria from the reference hospital, the Hospital Universitario de Burgos, in the region of Castilla y León, Spain. Patients will be followed-up by specialist physicians and Primary Health Care professionals. INCLUSION CRITERIA: - Men and women. - Age between 18 and 75 years old. - Diagnosed SARS-CoV-2 infection, by PCR and/or IgM+ antibody test and/or antigen test. - Clinical diagnosis of lung involvement: (respiratory symptoms +/- pathological auscultation +/- O2 desaturation) - Chest X-ray with mild-moderate alterations or normal. - Patients who give their verbal informed consent in front of witnesses, which will be reflected in the patients' medical records. EXCLUSION CRITERIA: - Oxygen desaturation below 93% or P02 < 62. - Moderate-severe dyspnea or significant respiratory or general deterioration that makes admission advisable. - Chest X-ray with multifocal infiltrates. - Insulin-dependent diabetes with poor control or glycaemia in the emergency room test greater than 300 mg/ml (fasting or not). - Other significant comorbidities: Severe renal failure (creatinine clearance < 30 mL/min); cirrhosis or chronic liver disease, poorly controlled hypertension. - Heart rhythm disturbances (including prolonged QT). - Severe immunosuppression (HIV infection, long-term use of immunosuppressive agents); cancer. - Pregnant or breast-feeding women. - Patients under use of glucocorticoids for other diseases. - History of allergy or intolerance to any of the drugs in the study (prednisone, azithromycin or hydroxychloroquine). - Patients who took one or more of the study drugs in the 7 days prior to study inclusion. - Patients taking non-suppressible drugs with risk of QT prolongation or significant interactions. - Patients unwilling or unable to participate until study completion. - Participation in another study. INTERVENTION AND COMPARATOR: Eligible patients will be randomized to receive standard outpatient treatment only (group 1) or standard outpatient treatment plus prednisone (group 2). - Group 1: paracetamol 1 g/8 h (on demand) + hydroxychloroquine 400 mg/12h the first day, 200 mg/12 h for 4 days + azithromycin 500 mg/24h for 5 days. - Group 2: paracetamol 1 g/8 h (on demand) + hydroxychloroquine 400 mg/12h the first day, 200 mg/12 h for 4 days + azithromycin 500 mg/24h for 5 days + prednisone 60 mg / 24 h for 3 days, 30 mg / 24 h for 3 days and 15 mg / 24 h for 3 days. MAIN OUTCOMES: If the patient requires ambulatory observation, according to the protocol established in this respect in the Emergency Department, meets all the criteria for inclusion and none for exclusion, data will be taken by the person responsible on the data collection sheet. The main result is admission after 30 days. Secondary outcomes are 30-day ICU admission and hospital stay. The safety variable will be the occurrence of clinical symptoms or delirium related to the steroids. Also, the possible decompensations of diabetes will be measured. All tests will be on an intention-to-treat basis. RANDOMISATION: Treatment will be assigned according to stratified randomization by the presence or absence of radiological data of lung involvement (previously performed by random sequence 1:1 generated with Epidat and kept hidden by opaque, sealed envelopes, which will only be opened after inclusion and basal measurement). BLINDING (MASKING): Participants, caregivers and personnel responsible for outcomes measurement will not be blinded to group assignment, once the patient is included and the basal measurement performed, as per protocol design. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The percentage of patients with incipient lung involvement is unknown, but given that pulmonary involvement already exists it is estimated to be around 20%. We consider that the intervention could reduce this percentage to 5%, so the necessary sample size would be 200 subjects (100 per group), with a power of 80% and an estimated loss percentage of 10%. TRIAL STATUS: The protocol with code TAC-COVID-19, version 2.0 on date: April 16, 2020 is approved by the Spanish Drug Agency (AEMPS) and the local Ethics Committee. The trial is in the recruitment phase. Recruitment began 19 April, 2020 and is anticipated to be complete by April 2021. TRIAL REGISTRATION: The trial was registered under the title "OUTPATIENT TREATMENT OF EARLY PULMONARY COVID19 WITH CORTICOSTEROIDS AS AN OPPORTUNITY TO MODIFY THE COURSE OF THE DISEASE" with EudraCT number 2020-001622-64 , registered on 3 April 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Title: Part II. High-dose methotrexate with leucovorin rescue for severe COVID-19: An immune stabilization strategy for SARS-CoV-2 induced ‘PANIC’ attack() Content: Here, in Part II of a duology on the characterization and potential treatment for COVID-19, we characterize the application of an innovative treatment regimen for the prevention of the transition from mild to severe COVID-19, as well as detail an intensive immunotherapy intervention hypothesis. We propose as a putative randomized controlled trial that high-dose methotrexate with leucovorin (HDMTX-LR) rescue can abolish ‘PANIC’, thereby ‘left-shifting’ severe COVID-19 patients to the group majority of those infected with the SARS-CoV-2 virus, who are designated as having mild, even asymptomatic, disease. HDMTX-LR is endowed with broadly pleiotropic properties and is a repurposed, generic, inexpensive, and widely available agent which can be administered early in the course of severe COVID-19 thus rescuing the critical and irreplaceable gas-exchange alveoli. Further, we describe a preventative treatment intervention regimen for those designated as having mild to moderate COVID-19 disease, but who exhibit features which herald the transition to the severe variant of this novel Coronavirus. Both of our proposed hypothesis-driven questions should be urgently subjected to rigorous assessment in the context of randomized controlled trials, in order to confirm or refute the contention that the approaches characterized herein, are in fact capable of exerting mitigating, if not abolishing, effects upon the SARS-CoV-2 triggering of the ‘PANIC Attack’. Confirmation of our immunotherapy hypothesis would have far-reaching ramifications for the current pandemic, along with yielding invaluable lessons from which we can more effectively prepare for the next challenge to global health.

Title: Psoriasis and COVID 19: A narrative review with treatment considerations Content: COVID‐19 is a highly contagious respiratory infection caused by severe acute respiratory syndrome coronavirus 2. COVID‐19 outbreak, has been declared a pandemic by the World Health Organization on March, 2020. The pandemic has affected the management of psoriasis, not only for those who are under treatment but also for those who are about to begin a new therapy to control their disease. An increasing number of studies in the current literature have focused on the relationship between psoriasis and COVID 19 from different perspectives. This narrative review includes searching the PubMed and Web of Science databases using the keywords "psoriasis,”, “psoriatic arthritis”, "coronavirus", "COVID 19" and "SARS‐Cov‐2". The search was supplemented by manual searching of reference lists of included articles. A total of 11 relevant original investigations and 6 case studies was identified. The search was updated in May 2019. Due to the absence of randomized controlled trials, it is not likely to have a robust evidence‐based approach to psoriasis management in the era of COVID‐19. However, current literature may provide some clues for safety considerations. Conventional immunosuppressive therapies such as methotrexate and cyclosporine, and anti TNF agents should not be preferred due to increased risk of infection, especially in high‐risk areas. The use of cyclosporine may pose additional risk due to the side effect of hypertension, which has been reported to be associated with susceptibility to severe COVID‐19. Considering that current literature has provide no conclusive evidence that biologics increase the risk of COVID‐19, withdrawal of these agents should be reserved for patients with COVID 19 symptoms. The treatment approach should be personalized, considering the advantages and disadvantages for each case separately. This article is protected by copyright. All rights reserved.

Title: COVID-19 Treatment: Close to a Cure? - A Rapid Review of Pharmacotherapies for the Novel Coronavirus Content: Currently, there is no approved therapy for COVID-19. The World Health Organization therefore endorse supportive care only. However, frontline clinicians and researchers have been experimenting with several virus-based and host-based therapeutics since the outbreak in China. China's National Health Commission has issued the first COVID-19 Treatment Guideline with therapy suggestions (7th edition attached) which inspired following clinical studies worldwide. Major therapeutics are evaluated in this review. Key evidence from in vitro researches, animal models and clinical researches in emerging coronaviruses are examined. Antiviral therapies remdesivir, lopinavir/ritonavir and umifenovir, if considered, could be initiated before the peak of viral replication for optimal outcomes. Ribavirin may be beneficial as an add-on therapy and is ineffective as a monotherapy. Corticosteroids use should be limited to indicating comorbidities. IVIG is not recommended due to lack of data in COVID-19. Xuebijing may benefit patients with complications of bacterial pneumonia or sepsis. The efficacy of interferon is unclear due to conflicting outcomes in coronavirus studies. Chloroquine and hydroxychloroquine have shown in vitro inhibition of SARS-CoV-2, and the studies on clinical efficacy and whether the benefits outweigh the risk of dysrhythmias remain inconclusive. For patients who developed cytokine release syndrome, interleukin-6 inhibitors may be beneficial.

Title: Emerging patterns of hypercoagulability associated with critical COVID-19: A review Content: Abstract While the COVID-19 pandemic sweeps the world, much evidence is being gathered regarding its novel pathological mechanisms. It is the authors’ clinical experience that patients in the intensive care unit suffering from COVID-19 are extremely pro-coagulable, with venous and arterial thromboembolism frequently observed, and losses of vascular access lines and filtration circuits to thrombosis now commonplace. Here, we explore the evidence for hypercoagulability in this group, presenting evidence of both a localised pulmonary hypercoagulability, and a systemic hypercoagulability resulting in thrombosis distant to the pulmonary vasculature. Furthermore, we discuss the possible risk factors exacerbated by, or selected for in COVID-19. We review the available evidence for use of plasma D-dimer as a prognostic marker, exploring the possibility that it acts as a marker of a COVID-19-associated hypercoagulability. We review the evidence for a pro-coagulant subtype of disseminated intravascular coagulation, discussing its clinical significance. Finally, we discuss the current evidence surrounding treatment of COVID-19 hypercoagulability, including prophylactic and treatment-dose heparin, thrombolytic agents, antiplatelet agents, and direct thrombin inhibitors, among others. We suggest areas in which further investigation is urgently needed to reduce the startling incidence of thrombosis in this group, a complication no doubt contributing to morbidity and mortality.

Title: Outpatient treatment of COVID-19 with steroids in the phase of mild pneumonia without the need for admission as an opportunity to modify the course of the disease: A structured summary of a randomised controlled trial Content: OBJECTIVES: The aim of this study is to explore the effectiveness and safety of oral corticosteroids (prednisone) in the treatment of early stage SARS-Cov-2 pneumonia in patients who do not yet meet hospital admission criteria. TRIAL DESIGN: Randomized clinical trial, controlled, open, parallel group, to evaluate the effectiveness of steroids in adult patients with confirmed COVID-19, with incipient pulmonary involvement, without hospital admission criteria. Patients will be stratified by the presence or not of radiological data on pneumonia. PARTICIPANTS: We will include patients with early stage SARS-Cov-2 pneumonia who do not meet hospital admission criteria from the reference hospital, the Hospital Universitario de Burgos, in the region of Castilla y León, Spain. Patients will be followed-up by specialist physicians and Primary Health Care professionals. Inclusion criteria: - Men and women. - Age between 18 and 75 years old. - Diagnosed SARS-CoV-2 infection, by PCR and/or IgM+ antibody test and/or antigen test. - Clinical diagnosis of lung involvement: (respiratory symptoms +/- pathological auscultation +/- O2 desaturation) - Chest X-ray with mild-moderate alterations or normal. - Patients who give their verbal informed consent in front of witnesses, which will be reflected in the patients’ medical records. Exclusion criteria: - Oxygen desaturation below 93% or P0(2) < 62. - Moderate-severe dyspnea or significant respiratory or general deterioration that makes admission advisable. - Chest X-ray with multifocal infiltrates. - Insulin-dependent diabetes with poor control or glycaemia in the emergency room test greater than 300 mg/ml (fasting or not). - Other significant comorbidities: Severe renal failure (creatinine clearance < 30 mL/min); cirrhosis or chronic liver disease, poorly controlled hypertension. - Heart rhythm disturbances (including prolonged QT). - Severe immunosuppression (HIV infection, long-term use of immunosuppressive agents); cancer. - Pregnant or breast-feeding women. - Patients under use of glucocorticoids for other diseases. - History of allergy or intolerance to any of the drugs in the study (prednisone, azithromycin or hydroxychloroquine). - Patients who took one or more of the study drugs in the 7 days prior to study inclusion. - Patients taking non-suppressible drugs with risk of QT prolongation or significant interactions. - Patients unwilling or unable to participate until study completion. - Participation in another study. INTERVENTION AND COMPARATOR: Eligible patients will be randomized to receive standard outpatient treatment only (group 1) or standard outpatient treatment plus prednisone (group 2). - Group 1: paracetamol 1 g/8 h (on demand) + hydroxychloroquine 400 mg/12h the first day, 200 mg/12 h for 4 days + azithromycin 500 mg/24h for 5 days. - Group 2: paracetamol 1 g/8 h (on demand) + hydroxychloroquine 400 mg/12h the first day, 200 mg/12 h for 4 days + azithromycin 500 mg/24h for 5 days + prednisone 60 mg / 24 h for 3 days, 30 mg / 24 h for 3 days and 15 mg / 24 h for 3 days. MAIN OUTCOMES: If the patient requires ambulatory observation, according to the protocol established in this respect in the Emergency Department, meets all the criteria for inclusion and none for exclusion, data will be taken by the person responsible on the data collection sheet. The main result is admission after 30 days. Secondary outcomes are 30-day ICU admission and hospital stay. The safety variable will be the occurrence of clinical symptoms or delirium related to the steroids. Also, the possible decompensations of diabetes will be measured. All tests will be on an intention-to-treat basis. RANDOMISATION: Treatment will be assigned according to stratified randomization by the presence or absence of radiological data of lung involvement (previously performed by random sequence 1:1 generated with Epidat and kept hidden by opaque, sealed envelopes, which will only be opened after inclusion and basal measurement). BLINDING (MASKING): Participants, caregivers and personnel responsible for outcomes measurement will not be blinded to group assignment, once the patient is included and the basal measurement performed, as per protocol design. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The percentage of patients with incipient lung involvement is unknown, but given that pulmonary involvement already exists it is estimated to be around 20%. We consider that the intervention could reduce this percentage to 5%, so the necessary sample size would be 200 subjects (100 per group), with a power of 80% and an estimated loss percentage of 10%. TRIAL STATUS: The protocol with code TAC-COVID-19, version 2.0 on date: April 16, 2020 is approved by the Spanish Drug Agency (AEMPS) and the local Ethics Committee. The trial is in the recruitment phase. Recruitment began 19 April, 2020 and is anticipated to be complete by April 2021. TRIAL REGISTRATION: The trial was registered under the title “OUTPATIENT TREATMENT OF EARLY PULMONARY COVID19 WITH CORTICOSTEROIDS AS AN OPPORTUNITY TO MODIFY THE COURSE OF THE DISEASE” with EudraCT number 2020-001622-64, registered on 3 April 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Title: The Rationale for Potential Pharmacotherapy of COVID-19 Content: On 11 March 2020, the coronavirus disease (COVID-19) was defined by the World Health Organization as a pandemic. Severe acute respiratory syndrome-2 (SARS-CoV-2) is the newly evolving human coronavirus infection that causes COVID-19, and it first appeared in Wuhan, China in December 2019 and spread rapidly all over the world. COVID-19 is being increasingly investigated through virology, epidemiology, and clinical management strategies. There is currently no established consensus on the standard of care in the pharmacological treatment of COVID-19 patients. However, certain medications suggested for other diseases have been shown to be potentially effective for treating this infection, though there has yet to be clear evidence. Therapies include new agents that are currently tested in several clinical trials, in addition to other medications that have been repurposed as antiviral and immune-modulating therapies. Previous high-morbidity human coronavirus epidemics such as the 2003 SARS-CoV and the 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) prompted the identification of compounds that could theoretically be active against the emerging coronavirus SARS-CoV-2. Moreover, advances in molecular biology techniques and computational analysis have allowed for the better recognition of the virus structure and the quicker screening of chemical libraries to suggest potential therapies. This review aims to summarize rationalized pharmacotherapy considerations in COVID-19 patients in order to serve as a tool for health care professionals at the forefront of clinical care during this pandemic. All the reviewed therapies require either additional drug development or randomized large-scale clinical trials to be justified for clinical use.

Title: Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients Content: Coronavirus 2019 (COVID-19) is a pandemic with substantial mortality and no accepted therapy. We report here on four consecutive outpatients with clinical characteristics (CDC case definition) of and/or laboratory-confirmed COVID-19 who were treated with high dose zinc salt oral lozenges. All four patients experienced significant improvement in objective and symptomatic disease measures after one day of high dose therapy suggesting that zinc therapy was playing a role in clinical recovery. A mechanism for zinc's effects is proposed based on previously published studies on SARS- CoV-1, and randomized controlled trials assessing zinc shortening of common cold duration. The limited sample size and study design preclude a definitive statement about the effectiveness of zinc as a treatment for COVID-19 but suggest the variables to be addressed to confirm these initial findings in future trials.

Title: Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients. Content: Coronavirus 2019 (COVID-19) is a pandemic with substantial mortality and no accepted therapy. We report here on four consecutive outpatients with clinical characteristics (CDC case definition) of and/or laboratory-confirmed COVID-19 who were treated with high dose zinc salt oral lozenges. All four patients experienced significant improvement in objective and symptomatic disease measures after one day of high dose therapy suggesting that zinc therapy was playing a role in clinical recovery. A mechanism for zinc's effects is proposed based on previously published studies on SARS- CoV-1, and randomized controlled trials assessing zinc shortening of common cold duration. The limited sample size and study design preclude a definitive statement about the effectiveness of zinc as a treatment for COVID-19 but suggest the variables to be addressed to confirm these initial findings in future trials.

Title: Effectiveness and Safety of Glucocorticoids to Treat COVID-19: A Rapid Review and Meta-Analysis Content: Background: Glucocorticoids are widely used in the treatment of various pulmonary inflammatory diseases, but they are also often accompanied by significant adverse reactions. Published guidelines point out that low dose and short duration systemic glucocorticoid therapy may be considered for patients with rapidly progressing COVID-19 while the evidence is still limited. Methods: We comprehensively searched electronic databases and supplemented the screening by conducting a manual search. We included RCTs and cohort studies evaluating the effectiveness and safety of glucocorticoids in children and adults with COVID-19, SARS and MERS, and conducted meta-analyses of the main indicators that were identified in the studies. Results: Our search retrieved 23 studies, including one RCT and 22 cohort studies, with a total of 13,815 patients. In adults with COVID-19, the use of systemic glucocorticoid did not reduce mortality (RR=2.00, 95% CI: 0.69 to 5.75, I 2=90.9%) or the duration of lung inflammation (WMD=-1 days, 95% CI: -2.91 to 0.91), while a significant reduction was found in the duration of fever (WMD=-3.23 days, 95% CI: -3.56 to -2.90). In patients with SARS, glucocorticoids also did not reduce the mortality (RR=1.52, 95% CI: 0.89 to 2.60, I2=84.6%), duration of fever (WMD=0.82 days, 95% CI: -2.88 to 4.52, I2=97.9%) or duration of lung inflammation absorption (WMD=0.95 days, 95% CI: -7.57 to 9.48, I2=94.6%). The use of systemic glucocorticoid therapy prolonged the duration of hospital stay in all patients (COVID-19, SARS and MERS). Conclusions: Glucocorticoid therapy was found to reduce the duration of fever, but not mortality, duration of hospitalization or lung inflammation absorption. Long-term use of high-dose glucocorticoids increased the risk of adverse reactions such as coinfections, so routine use of systemic glucocorticoids for patients with COVID-19 cannot be recommend. Keywords: COVID-19; glucocorticoids; meta-analysis; rapid review

Title: A COVID-19 pandemic guideline in evidence-based medicine Content: Data sources This review article scrutinised 16 clinical studies (clinical trials and observational studies) concerning coronavirus disease of 2019 (COVID-19). Additionally, 18 guidelines about the COVID-19 were reviewed and the key points were represented in this study. Study selection The review included human trials, in-vitro studies, review articles, and credible news reports about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 complications, treatment guidelines, management strategies, and epidemiological features. There were no exclusion criteria reported in this review and the included information was in English and Chinese languages. Data extraction and synthesis A descriptive review of the literature was conducted, taking a comprehensive approach. The paper consisted of three main parts: introduction, presentation, and management. The introduction part presented basic information about the SARS-CoV-2, its evolution and transmission, and the course of disease. The presentation section introduced the signs and symptoms, diagnosis, high risk groups, and complications of COVID-19. Eventually, some evidence was presented about the prevention, medical management, and measuring responses to the treatments in the management section. Results Based on the results of this study, non-pharmaceutical interventions, including strict social isolation and distancing measures, might reduce the spread of the SARS-CoV-2 by nearly 99.3 percent (reproduction number mitigating from 406 to 2.5 in 30 days). In the supportive management section, monitoring vital signs and neonatal feeding were stated as the most important factors to consider. For symptomatic neonates, medical management and intervention were mentioned as essential. It was claimed that for adults with mild infection, the best option would be home quarantine with further medical monitoring or hospitalisation if required. The following sequence was also suggested as early supportive therapy and monitoring: intravenous fluid administration, oxygen therapy, and application of corticosteroids. Management of critical patients with critical COVID-19 included admission to intensive care unit, use of continuous positive airway pressure and bi-level positive airway pressure in certain circumstances, endotracheal intubation, invasive mechanical ventilation, extracorporeal membrane oxygenation, and fluid resuscitation and vasopressors. Additionally, this study suggested oseltamivir, iopinavir, remdesivir, chloroquine, baricitinib, ruxolitinib, and fedratinib as possible drugs to help manage COVID-19. A soaring c-reactive protein level and decreased albumin content in the blood were reported to be associated with a deteriorating status in COVID-19 patients. To keep the number of exposures to a minimum, two separate viral clearance tests taken at least 24 hours apart, were stated as necessary laboratory results before the discharge of patients with COVID-19. Conclusions The study warns about possible exponential spread of COVID-19 and proposes to adhering to tighter restrictions of social distancing. Besides the clinical guidelines presented within the study, it also encourages further up-to-date and evidence-based management guidelines for patients with COVID-19.

Title: A COVID-19 pandemic guideline in evidence-based medicine Content: Data sources This review article scrutinised 16 clinical studies (clinical trials and observational studies) concerning coronavirus disease of 2019 (COVID-19). Additionally, 18 guidelines about the COVID-19 were reviewed and the key points were represented in this study.Study selection The review included human trials, in-vitro studies, review articles, and credible news reports about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 complications, treatment guidelines, management strategies, and epidemiological features. There were no exclusion criteria reported in this review and the included information was in English and Chinese languages.Data extraction and synthesis A descriptive review of the literature was conducted, taking a comprehensive approach. The paper consisted of three main parts: introduction, presentation, and management. The introduction part presented basic information about the SARS-CoV-2, its evolution and transmission, and the course of disease. The presentation section introduced the signs and symptoms, diagnosis, high risk groups, and complications of COVID-19. Eventually, some evidence was presented about the prevention, medical management, and measuring responses to the treatments in the management section.Results Based on the results of this study, non-pharmaceutical interventions, including strict social isolation and distancing measures, might reduce the spread of the SARS-CoV-2 by nearly 99.3 percent (reproduction number mitigating from 406 to 2.5 in 30 days). In the supportive management section, monitoring vital signs and neonatal feeding were stated as the most important factors to consider. For symptomatic neonates, medical management and intervention were mentioned as essential. It was claimed that for adults with mild infection, the best option would be home quarantine with further medical monitoring or hospitalisation if required. The following sequence was also suggested as early supportive therapy and monitoring: intravenous fluid administration, oxygen therapy, and application of corticosteroids. Management of critical patients with critical COVID-19 included admission to intensive care unit, use of continuous positive airway pressure and bi-level positive airway pressure in certain circumstances, endotracheal intubation, invasive mechanical ventilation, extracorporeal membrane oxygenation, and fluid resuscitation and vasopressors. Additionally, this study suggested oseltamivir, iopinavir, remdesivir, chloroquine, baricitinib, ruxolitinib, and fedratinib as possible drugs to help manage COVID-19. A soaring c-reactive protein level and decreased albumin content in the blood were reported to be associated with a deteriorating status in COVID-19 patients. To keep the number of exposures to a minimum, two separate viral clearance tests taken at least 24 hours apart, were stated as necessary laboratory results before the discharge of patients with COVID-19.Conclusions The study warns about possible exponential spread of COVID-19 and proposes to adhering to tighter restrictions of social distancing. Besides the clinical guidelines presented within the study, it also encourages further up-to-date and evidence-based management guidelines for patients with COVID-19.

Title: Treatment algorithm for COVID-19: a multidisciplinary point of view Content: The novel coronavirus (Sars-CoV-2) pandemic has spread rapidly, from December to the end of March, to 185 countries, and there have been over 3,000,000 cases identified and over 200,000 deaths. For a proportion of hospitalized patients, death can occur within a few days, mainly for adult respiratory distress syndrome or multi-organ dysfunction syndrome. In these patients, clinical signs and symptoms, as well as laboratory abnormalities, suggest a cytokine storm syndrome in response to the viral infection. No current targeted treatment is yet available for COVID-19, an unknown disease up to 2 months ago, which challenges doctors and researchers to find new drugs or reallocate other treatments for these patients. Since the beginning of the COVID-19 outbreak, a growing body of information on diagnostic and therapeutic strategies has emerged, mainly based on preliminary experience on retrospective studies or small case series. Antivirals, antimalarials, corticosteroids, biotechnological and small molecules, convalescent plasma and anticoagulants are among the drugs proposed for the treatment or in tested for COVID-19. Given the complexity of this new condition, a multidisciplinary management seems to be the best approach. Sharing and integrating knowledge between specialists, to evaluate the correct timing and setting of every treatment, could greatly benefit our patients. We reviewed the literature, combining it with our experiences and our specialist knowledge, to propose a management algorithm, correlating the clinical features with laboratory and imaging findings to establish the right timing for each treatment.

Title: The role of corticosteroids in the management of critically ill patients with coronavirus disease 2019 (COVID-19): A meta-analysis Content: Objective: There are no controlled studies on the role of systemic corticosteroids (CS) in patients with coronavirus disease 2019 (COVID-19). In the absence of high-quality evidence, understandably the recommendations from various organizations are cautious. Several randomized controlled trials are underway but shall take time to conclude. We therefore undertook a meta-analysis to ascertain the role of CS in the management of critically ill patients with COVID-19. Data Sources: Electronic databases, including Pubmed, Cochrane library and Embase, were searched, using the keywords of interest and the PICO search technique, from inception to 12th April 2020. Study Selection: Studies highlighting the use of CS in coronavirus infection with severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome (MERS) and COVID-19 were selected based on pre-determined inclusion criteria. Data extraction: Data was extracted into an excel sheet and transferred to comprehensive meta-analysis software version 3, Biostat Inc., Englewood, NJ, USA, for analysis. Data synthesis: Five studies with SARS-CoV-2 infection were included in the meta-analysis. The rate ratio (RR) for mortality in patients with SARS-CoV-2 infection was 1.26 (95% CI: 0.96-1.65, I2: 74.46), indicating lack of benefit of CS therapy on mortality in critically ill patients with COVID-19. The RR for mortality on analysis of the three studies that particularly reported on patients with significant pulmonary compromise secondary to SARS-CoV-2 infection was neutral (RR: 0.91, 95% CI: 0.63-1.33, I2: 63.38). Conclusions: The use of CS in critically ill patients with COVID-19 did not improve or worsen mortality. Pending further information from controlled studies, CS can be used in critically ill patients with COVID-19 with critical illness related corticosteroid insufficiency and moderate to severe ARDS without the risk of increased mortality.

Title: The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19 Content: Abstract The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has posed the world at a pandemic risk. Coronavirus-19 disease (COVID-19) is an infectious disease caused by SARS-CoV-2, which causes pneumonia, requires intensive care unit hospitalization in about 10% of cases and can lead to a fatal outcome. Several efforts are currently made to find a treatment for COVID-19 patients. So far, several anti-viral and immunosuppressive or immunomodulating drugs have demonstrated some efficacy on COVID-19 both in vitro and in animal models as well as in cases series. In COVID-19 patients a pro-inflammatory status with high levels of interleukin (IL)-1B, IL-1 receptor (R)A and tumor necrosis factor (TNF)-α has been demonstrated. Moreover, high levels of IL-6 and TNF-α have been observed in patients requiring intensive-care-unit hospitalization. This provided rationale for the use of anti-rheumatic drugs as potential treatments for this severe viral infection. Other agents, such as hydroxychloroquine and chloroquine might have a direct anti-viral effect. The anti-viral aspect of immunosuppressants towards a variety of viruses has been known since long time and it is herein discussed in the view of searching for a potential treatment for SARS-CoV-2 infection.

Title: Review of Emerging Pharmacotherapy for the Treatment of Coronavirus Disease 2019 Content: The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID‐19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacologic management of patients with COVID‐19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immunomodulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS‐CoV‐2. Critically ill patients with COVID‐19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID‐19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.

Title: Anti-Coagulant and Anti-Platelet Therapy in the COVID-19 Patient: A Best Practices Quality Initiative Across a Large Health System. Content: The coronavirus disease 2019 (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged health care systems and physicians worldwide to attempt to provide the best care to their patients with an evolving understanding of this unique pathogen. This disease and its worldwide impact have sparked tremendous interest in the epidemiology, pathogenesis, and clinical consequences of COVID-19. This accumulating body of evidence has centered around case series and often empiric therapies as controlled trials are just getting underway. What is clear is that patients appear to be at higher risk for thrombotic disease states including acute coronary syndrome (ACS), venous thromboembolism (VTE) such as deep vein thrombosis (DVT) or pulmonary embolism (PE), or stroke. Patients with underlying cardiovascular disease are also at higher risk for morbidity and mortality if infected. These patients are commonly treated with anticoagulation and/or antiplatelet medications and less commonly thrombolysis during hospitalization, potentially with great benefit but management of these medications can be difficult in potentially critically ill patients.In this paper, we review the current guidelines, consensus statements, and emerging evidence for a wide range of cardiovascular disease states with special focus on anticoagulant and antiplatelet therapy. Our goal is to provide guidance for treatment of the cardiovascular patient with COVID-19 in the face of a rapidly evolving understanding of this virus and its complications.Preamble:Anticoagulant and antiplatelet therapies are a major cause of inpatient morbidity and mortality. This is amplified in critically ill patients. COVID-19 patients present special challenges due to rapidly changing clinical status. In an effort to align practice patterns across a large health system (Jefferson Health 2,622 staffed inpatient beds and 319 intensive care unit (ICU) beds across 14 facilities), a task force was assembled to address the utilization of anti-thrombotic and anti-platelet therapy in COVID-19 positive or suspected patients. The task force incorporated experts in Cardiology, Vascular Medicine, Hematology, Vascular Surgery, Pharmacy, and Vascular Neurology. Current guidelines, consensus documents, and policy documents from specialty organizations were used to formulate health system recommendations. Our deliberations and treatment recommendations are summarized here.Objective:To provide guidance to the utilization of antithrombotic and antiplatelet therapies in patients with known or suspected COVID-19.

Title: Endocrine and metabolic aspects of the COVID-19 pandemic Content: COVID-19 infection has tremendously impacted our daily clinical practice as well as our social living organization. Virtually all organs and biological systems suffer from this new coronavirus infection, either because the virus targets directly specific tissues or because of indirect effects. Endocrine diseases are not an exception and some of endocrine organs are at risk of direct or indirect lesion by COVID-19. Although there is still no evidence of higher predisposition to contract the infection in patients with diabetes and/or obesity, the coexistence of these conditions contributes to a worse prognosis because both conditions confer an impaired immunologic system. Cytokines storm can be amplified by these two latter conditions thereby leading to multisystemic failure and death. Glycaemic control has been demonstrated to be crucial to avoiding long hospital stays, ICU requirement and also prevention of excessive mortality. Endocrine treatment modifications as a consequence of COVID-19 infection are required in a proactive manner, in order to avoid decompensation and eventual hospital admission. This is the case of diabetes and adrenal insufficiency in which prompt increase of insulin dosage and substitutive adrenal steroids through adoption of the sick day’s rules should be warranted, as well as easy contact with the health care provider through telematic different modalities. New possible endocrinological targets of COVID-19 have been recently described and warrant a full study in the next future.

Title: Three novel prevention, diagnostic, and treatment options for COVID-19 urgently necessitating controlled randomized trials Content: PURPOSE: Asymptomatic or minimally symptomatic infection with COVID-19 can result in silent transmission to large numbers of individuals, resulting in expansion of the pandemic with a global increase in morbidity and mortality. New ways of screening the general population for COVID-19 are urgently needed along with novel effective prevention and treatment strategies. HYPOTHESIS: A hypothetical three-part prevention, diagnostic, and treatment approach based on an up-to-date scientific literature review for COVID-19 is proposed. Regarding diagnosis, a validated screening questionnaire and digital app for COVID-19 could help identify individuals who are at risk of transmitting the disease, as well as those at highest risk for poor clinical outcomes. Global implementation and online tracking of vital signs and scored questionnaires that are statistically validated would help health authorities properly allocate essential health care resources to test and isolate those at highest risk for transmission and poor outcomes. Second, regarding prevention, no validated protocols except for physical distancing, hand washing, and isolation exist, and recently ivermectin has been published to have anti-viral properties against COVID-19. A randomized trial of ivermectin, and/or nutraceuticals that have been published to support immune function including glutathione, vitamin C, zinc, and immunomodulatory supplements (3,6 Beta glucan) could be beneficial in preventing transmission or lessening symptomatology but requires statistical validation. Third, concerning treatment, COVID-19 induced inflammation and "cytokine storm syndrome" with hemophagocytic lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) have resulted in extreme morbidity and mortality in those with certain comorbidities, secondary to "acute respiratory distress syndrome" (ARDS) and multiorgan dysfunction with disseminated intravascular coagulation (DIC). Deficiency in red blood cell, serum and alveolar glutathione has been published in the medical literature for ARDS, as well as viral and bacterial pneumonias, resulting from increased levels of free radical/oxidative stress. A randomized controlled trial of blocking NF-κB and cytokine formation using glutathione precursors (N-acetyl-cysteine [NAC] and alpha lipoic acid) and PO/IV glutathione with associated anti-viral effects should be performed, along with an evaluation of Nrf2 activators (curcumin, sulforaphane glucosinolate) which have been scientifically proven to lower inflammation. Since high mortality rates from sepsis induced DIC due to COVID-19 infection has also been associated with thrombotic events and elevated levels of D-dimer, randomized controlled trials of using anticoagulant therapy with heparin is urgently required. This is especially important in patients on ventilators who have met certain sepsis induced coagulopathy (SIC) criteria. The use of acetazolamide with or without sildenafil also needs to be explored with or without heparin, since increased oxygen delivery to vital organs through prevention of thrombosis/pulmonary emboli along with carbonic anhydrase inhibition may help increase oxygenation and prevent adverse clinical outcomes. CONCLUSION AND IMPLICATIONS: A three-part prevention, diagnostic, and treatment plan is proposed for addressing the severe complications of COVID-19. Digital monitoring of symptoms to clinically diagnose early exposure and response to treatment; prevention with ivermectin as well as nutritional therapies that support a healthy immune response; treatment with anti-inflammatory therapies that block NF-κB and activate Nrf2 pathways, as well as novel therapies that address COVID-19 pneumonia and ARDS with DIC including anticoagulation and/or novel respiratory therapies with or without acetazolamide and sildenafil. These three broad-based interventions urgently need to be subjected to randomized, controlled trials.