A Potential Role of the Spike Protein in Neurodegenerative Diseases: A Narrative Review.

Human prion protein and prion-like protein misfolding are widely recognized as playing a causal role in many neurodegenerative diseases. Based on in vitro and in vivo experimental evidence relating to prion and prion-like disease, we extrapolate from the compelling evidence that the spike glycoprotein of SARS-CoV-2 contains extended amino acid sequences characteristic of a prion-like protein to infer its potential to cause neurodegenerative disease. We propose that vaccine-induced spike protein synthesis can facilitate the accumulation of toxic prion-like fibrils in neurons. We outline various pathways through which these proteins could be expected to distribute throughout the body. We review both cellular pathologies and the expression of disease that could become more frequent in those who have undergone mRNA vaccination. Specifically, we describe the spike protein's contributions, via its prion-like properties, to neuroinflammation and neurodegenerative diseases; to clotting disorders within the vasculature; to further disease risk due to suppressed prion protein regulation in the context of widely prevalent insulin resistance; and to other health complications. We explain why these prion-like characteristics are more relevant to vaccine-related mRNA-induced spike proteins than natural infection with SARS-CoV-2. We note with an optimism an apparent loss of prion-like properties among the current Omicron variants. We acknowledge that the chain of pathological events described throughout this paper is only hypothetical and not yet verified. We also acknowledge that the evidence we usher in, while grounded in the research literature, is currently largely circumstantial, not direct. Finally, we describe the implications of our findings for the general public, and we briefly discuss public health recommendations we feel need urgent consideration. An earlier version of this article was previously posted to the Authorea preprint server on August 16, 2022.

Mitogen Activated Protein Kinase (MAPK) Activation, p53, and Autophagy Inhibition Characterize the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein Induced Neurotoxicity.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and prions use common pathogenic pathways to induce toxicity in neurons. Infectious prions rapidly activate the p38 mitogen activated protein kinase (MAPK) pathway, and SARS-CoV-2 spike proteins rapidly activate both the p38 MAPK and c-Jun NH2-terminal kinase (JNK) pathways through toll-like receptor signaling, indicating the potential for similar neurotoxicity, causing prion and prion-like disease. In this review, we analyze the roles of autophagy inhibition, molecular mimicry, elevated intracellular p53 levels and reduced Wild-type p53-induced phosphatase 1 (Wip1) and dual-specificity phosphatase (DUSP) expression in neurons in the disease process. The pathways induced by the spike protein via toll-like receptor activation induce both the upregulation of PrPC (the normal isoform of the prion protein, PrP) and the expression of ß amyloid. Through the spike-protein-dependent elevation of p53 levels via ß amyloid metabolism, increased PrPC expression can lead to PrP misfolding and impaired autophagy, generating prion disease. We conclude that, according to the age of the spike protein-exposed patient and the state of their cellular autophagy activity, excess sustained activity of p53 in neurons may be a catalytic factor in neurodegeneration. An autoimmune reaction via molecular mimicry likely also contributes to neurological symptoms. Overall results suggest that neurodegeneration is in part due to the intensity and duration of spike protein exposure, patient advanced age, cellular autophagy activity, and activation, function and regulation of p53. Finally, the neurologically damaging effects can be cumulatively spike-protein dependent, whether exposure is by natural infection or, more substantially, by repeated mRNA vaccination.

Inpatient Mortality According to Level of Respiratory Support Received for Severe Acute Respiratory Syndrome Coronavirus 2 (Coronavirus Disease 2019) Infection: A Prospective Multicenter Study.

OBJECTIVES: To describe patients according to the maximum degree of respiratory support received and report their inpatient mortality due to coronavirus disease 2019. DESIGN: Analysis of patients in the Coracle registry from February 22, 2020, to April 1, 2020. SETTING: Hospitals in the Piedmont, Lombardy, Tuscany, and Lazio regions of Italy. PATIENTS: Nine-hundred forty-eight patients hospitalized for coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 948 patients, 122 (12.87%) received invasive ventilation, 637 (67.19%) received supplemental oxygen only, and 189 (19.94%) received no respiratory support. The median (quartile 1-quartile 3) age was 65 years (54-76.59 yr), and there was evidence of differential respiratory treatment by decade of life (p = 0.0046); patients greater than 80 years old were generally not intubated. There were 606 men (63.9%) in this study, and they were more likely to receive respiratory support than women (p < 0.0001). The rate of in-hospital death for invasive ventilation recipients was 22.95%, 12.87% for supplemental oxygen recipients, and 7.41% for those who received neither (p = 0.0004). A sensitivity analysis of the 770 patients less than 80 years old revealed a lower, but similar mortality trend (18.02%, 8.10%, 5.23%; p = 0.0008) among the 14.42%, 65.71%, and 19.87% of patients treated with mechanical ventilation, supplemental oxygen only, or neither. Overall, invasive ventilation recipients who died were significantly older than those who survived (median age: 68.5 yr [60-81.36 yr] vs 62.5 yr [55.52-71 yr]; p = 0.0145). CONCLUSIONS: Among patients hospitalized for coronavirus disease 2019, 13% received mechanical ventilation, which was associated with a mortality rate of 23%.

Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients.

Aims: Ivermectin is a safe, inexpensive and effective early COVID-19 treatment validated in 20+ random, controlled trials. Having developed combination therapies for Helicobacter pylori, the authors present a highly effective COVID-19 therapeutic combination, stemming from clinical observations. Patients & methods: In 24 COVID-19 subjects refusing hospitalization with high-risk features, hypoxia and untreated moderate to severe symptoms averaging 9 days, the authors administered this novel combination of ivermectin, doxycycline, zinc and vitamins D and C. Results & conclusions: All subjects resolved symptoms (in 11 days on average), and oxygen saturation improved in 24 h (87.4% to 93.1%; p = 0.001). There were no hospitalizations or deaths, less than (p < 0.002 or 0.05, respectively) background-matched CDC database controls. Triple combination therapy is safe and effective even when used in outpatients with moderate to severe symptoms. Clinical Trial Registration: NCT04482686 (ClinicalTrial.gov).

Early multidrug treatment of SARS-CoV-2 infection (COVID-19) and reduced mortality among nursing home (or outpatient/ambulatory) residents.

The outbreak of COVID-19 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread all over the world with tremendous morbidity and mortality in the elderly. In-hospital treatment addresses the multifaceted nature of the illness including initial viral replication, cytokine storm, and endothelial injury with thrombosis. We identified nine reports of early treatment outcomes in COVID-19 nursing home patients. Multi-drug therapy including hydroxychloroquine with one or more anti-infectives, corticosteroids, and antithrombotic anti-blood clotting agents can be extended to seniors in the nursing home setting without hospitalization. Data from nine studies found hydroxychloroquine-based multidrug regimens were associated with a statistically significant > 60% reduction in mortality. Going forward, we conclude that early empiric treatment for the elderly with COVID-19 in the nursing home setting (or similar congregated settings with elderly residents/patients e.g. LTF or ALF) has a reasonable probability of success and acceptable safety. This group remains our highest at-risk group and warrants acute treatment focus prior to symptoms worsening. Given the rapidity and severity of SARS-CoV-2 outbreaks in nursing homes, in-center treatment of acute COVID-19 patients is a reasonable strategy to reduce the risks of hospitalization and death. If elderly high-risk patients in such congregated nursing home type settings are allowed to worsen with no early treatment, they may be too sick and fragile to benefit from in-hospital therapeutics and are at risk for pulmonary failure, life-ending micro-thrombi of the lungs, kidneys etc. The issue is timing of therapeutics, and we argue that early treatment before hospitalization, is the right time and can potentially save lives, especially among our higher-risk elderly populations hit hardest by severe illness and death from COVID-19. We must reiterate, we are talking about 'early' treatment before the disease is far along in the disease sequelae where the patient then needs hospitalization and aggressive interventions. We are referring to the initial days e.g. day one, post infection when symptoms emerge or there is strong clinical suspicion. This early therapeutic option deserves serious and urgent consideration by the medical establishment and respective decision-makers. Doctors must be allowed their clinical discretion in how they optimally treat their patients. Doctors must be brave and trust their skilled judgements and do all to save the lives of their patients. We therefore hypothesize that early outpatient ambulatory treatment, once initiated as soon as symptoms begin in high-risk positive persons, would significantly reduce hospitalizations and prevent deaths. Specifically, the provision of early multi-drug sequenced therapy with repurposed drugs will reduce hospitalization and death in elderly patients being cared for in long-term-care facilities. The most important implications of our hypothesis are: 1) hospitalizations and deaths would be reduced 2) transmission would be reduced due to the mitigation of symptoms and 3) recovery following infection and treatment provides for natural exposure immunity that is broad based, durable, and robust (helping towards natural immunity within the population). The end result is reduced strain on hospitals and systems that would allow for other non-COVID illnesses to receive care.

Screening, detection, and management of heart failure in the SARS-CoV2 (COVID-19) pandemic.

Observational studies suggest that a heart failure (HF) diagnosis carries a poor prognosis in subjects with severe SARS-CoV2 (COVID-19) infection, but it is unknown whether this association reflects direct myocardial damage due to COVID-19 or the consequence of preexisting cardiac defects and related cardiovascular disease (CVD) risk burden. Although the close relation between CVD and COVID-19 outcomes is well established, contrasting data exists about the occurrence of HF complications during COVID-19 infection. Therefore, a specific algorithm focused on diagnostic differentiation in acute patients distinguishing between acute HF and acute respiratory distress syndrome related to COVID-19 is needed. Further, several concerns exist for the management of patients with an uncertain diagnosis and acute dyspnea, the exact relationship existing between COVID-19 and HF. Therefore, the treatment for subjects with both COVID-19 and HF and which criteria may be defined for domiciliary or hospital management, remain poorly defined. Herein, we describe practices to be adopted in order to address these concerns and avoid further virus spread among patients, l and their familiars involved in such patients' care.

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).

The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.

Clinical outcomes after early ambulatory multidrug therapy for high-risk SARS-CoV-2 (COVID-19) infection.

There is an emergency need for early ambulatory treatment of Coronavirus Disease 2019 (COVID-19) in acutely ill patients in an attempt to reduce disease progression and the risks of hospitalization and death. Such management should be applied in high-risk patients age > 50 years or with one or more medical problems including cardiovascular disease. We evaluated a total of 922 outpatients from March to September 2020. All patients underwent contemporary real-time polymerase chain reaction (PCR) assay tests from anterior nasal swab samples. Patients age 50.5 ± 13.7 years (range 12 to 89), 61.6% women, at moderate or high risk for COVID-19 received empiric management via telemedicine. At least two agents with antiviral activity against SARS-CoV-2 (zinc, hydroxychloroquine, ivermectin) and one antibiotic (azithromycin, doxycycline, ceftriaxone) were used along with inhaled budesonide and/or intramuscular dexamethasone consistent with the emergent science on early COVID-19 treatment. For patients with high severity of symptoms, urgent in-clinic administration of albuterol nebulizer, inhaled budesonide, and intravenous volume expansion with supplemental parenteral thiamine 500 mg, magnesium sulfate 4 grams, folic acid 1 gram, vitamin B12 1 mg. A total of 320/922 (34.7%) were treated resulting in 6/320 (1.9%) and 1/320 (0.3%) patients that were hospitalized and died, respectively. We conclude that early ambulatory (not hospitalized, treated at home), multidrug therapy is safe, feasible, and associated with low rates of hospitalization and death. Early treatment should be considered for high-risk patients as an emergency measure while we await randomized trials and guidelines for ambulatory management.

Favipiravir and the Need for Early Ambulatory Treatment of SARS-CoV-2 Infection (COVID-19).

It is becoming increasingly clear that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), like most human viral infections, will require multiple drugs in combination to treat COVID-19 illness. In this issue of the Journal, Doi and colleagues describe successful treatment of patients with early COVID-19 with favipiravir, an oral polymerase inhibitor, to rapidly and substantially clear SARS-CoV-2 from nasal secretions irrespective if it was started relatively early or later within the first week of infection. These data support the concept that favipiravir could be paired with at least one more off-target antiviral agent (doxycycline, azithromycin, or ivermectin) followed by corticosteroids and antithrombotics to prevent COVID-19 hospitalization and death in those over age 50 and/or those with one or more comorbidities. Clinical trials and advanced practice should immediately pivot to combination/sequential drug therapy for ambulatory COVID-19 illness.

Delays in Presentation in Patients With Acute Myocardial Infarction During the COVID-19 Pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has had a major impact on the behavior of patients, as well as on the delivery of healthcare services. With older and more medically vulnerable people tending to stay at home to avoid contracting the virus, it is unclear how the behavior of people with acute myocardial infarction (AMI) has changed. The aim of this study was to determine if delays in presentation and healthcare service delivery for AMI exist during the COVID-19 pandemic compared to the same period a year prior. METHODS: In this single-center, retrospective study, we evaluated patients admitted with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI) during early months of the COVID-19 pandemic (March 11, 2020 to April 20, 2020) compared to patients admitted with same diagnosis during the same period a year prior. RESULTS: There were 30 and 62 patients who presented with NSTEMI in the pandemic and pre-pandemic eras, respectively. The median pain-to-door time was significantly larger during the pandemic compared to pre-pandemic era (1,885 (880, 5,732) vs. 606 (388, 944) min, P < 0.0001). There was a significant delay in door-to-reperfusion time during the pandemic with a median time of 332 (182, 581) vs. 194 (92, 329) min (P = 0.0371). There were 24 (80%) and 25 (42%) patients who presented after 12 h of pain onset in pandemic and pre-pandemic eras, respectively (P = 0.0006). There were 47 and 60 patients who presented with STEMI during the pandemic timeframe of study and pre-pandemic timeframe, respectively. The median pain-to-door time during the pandemic was significantly larger than that of the pre-pandemic (620 (255, 1,500) vs. 349 (146, 659) min, P = 0.0141). There were 22 (47%) and 14 (24%) patients who presented after 12 h of pain onset in the pandemic and pre-pandemic eras, respectively (P = 0.0127). There was not a significant delay in door-to-reperfusion time (P = 0.9833). There were no differences in in-hospital death, stroke, or length of hospitalization between early and late presenters, as well as between pandemic and pre-pandemic eras. CONCLUSIONS: In conclusion, this study found that patients waited significantly longer during the pandemic to seek medical treatment for AMI compared to before the pandemic, and that pandemic-specific protocols may delay revascularization for NSTEMI patients. These findings resulted in more than a threefold increase from the onset of symptoms to revascularization increasing the risks for future complications such as left ventricular dysfunction and cardiovascular death. Efforts should be made to increase patients' awareness regarding consequences of delayed presentation, and to find a balance between hospital evaluation strategies and goals of minimizing total ischemic time.

Antecedent Administration of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists and Survival After Hospitalization for COVID-19 Syndrome.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes the angiotensin-converting enzyme-2 (ACE-2) receptor to enter human cells. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARB) are associated with ACE-2 upregulation. We hypothesized that antecedent use of ACEI/ARB may be associated with mortality in coronavirus disease 2019 (COVID-19). Methods and Results We used the Coracle registry, which contains data of patients hospitalized with COVID-19 in 4 regions of Italy, and restricted analyses to those ≥50 years of age. The primary outcome was in-hospital mortality. Among these 781 patients, 133 (17.0%) used an ARB and 171 (21.9%) used an ACEI. While neither sex nor smoking status differed by user groups, patients on ACEI/ARB were older and more likely to have hypertension, diabetes mellitus, and congestive heart failure. The overall mortality rate was 15.1% (118/781) and increased with age (PTrend<0.0001). The crude odds ratios (ORs) for death for ACEI users and ARB users were 0.98, 95% CI, 0.60-1.60, P=0.9333, and 1.13, 95% CI, 0.67-1.91, P=0.6385, respectively. After adjusting for age, hypertension, diabetes mellitus, and congestive heart failure, antecedent ACEI administration was associated with reduced mortality (OR, 0.55; 95% CI, 0.31-0.98, P=0.0436); a similar, but weaker trend was observed for ARB administration (OR, 0.58; 95% CI, 0.32-1.07, P=0.0796). Conclusions In those aged ≥50 years hospitalized with COVID-19, antecedent use of ACEI was independently associated with reduced risk of inpatient death. Our findings suggest a protective role of renin-angiotensin-aldosterone system inhibition in patients with high cardiovascular risk affected by COVID-19.

COVID-19-Associated Systemic Thromboembolism: A Case Report and Review of the Literature.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is a pandemic that has affected >188 countries, involved >24 million people, and caused >840,000 deaths. COVID-19, in its severe form, presents as acute respiratory distress syndrome (ARDS), shock, and multiorgan failure. Thrombotic microangiopathy of the lungs and kidneys has been observed in these patients. Elevated D-dimer levels have been observed in people with serious COVID-19 illness, and this could be helpful in guiding treatment with anticoagulation in these patients. OBJECTIVE: To analyze the role of anticoagulation as a treatment modality for COVID-19. METHODS: We present the unique case of a COVID-19 patient who developed sepsis, ARDS, acute kidney injury, and deep-vein thrombosis (DVT), who was deteriorating clinically. She was treated with anticoagulation. RESULTS: There was rapid recovery after treatment with systemic anticoagulation. CONCLUSIONS: Systemic anticoagulation could prove to be essential in the treatment of CO-VID-19. Further studies are required to assess its role in improving long-term morbidity and mortality in these patients.

Vitamin D deficiency in association with endothelial dysfunction: Implications for patients with COVID-19.

There is emerging evidence to suggest that vitamin D deficiency is associated with adverse outcomes in COVID-19 patients. Conversely, vitamin D supplementation protects against an initial alveolar diffuse damage of COVID-19 becoming progressively worse. The mechanisms by which vitamin D deficiency exacerbates COVID-19 pneumonia remain poorly understood. In this review we describe the rationale of the putative role of endothelial dysfunction in this event. Herein, we will briefly review (1) anti-inflammatory and anti-thrombotic effects of vitamin D, (2) vitamin D receptor and vitamin D receptor ligand, (3) protective role of vitamin D against endothelial dysfunction, (4) risk of vitamin D deficiency, (5) vitamin D deficiency in association with endothelial dysfunction, (6) the characteristics of vitamin D relevant to COVID-19, (7) the role of vitamin D on innate and adaptive response, (8) biomarkers of endothelial cell activation contributing to cytokine storm, and (9) the bidirectional relationship between inflammation and homeostasis. Finally, we hypothesize that endothelial dysfunction relevant to vitamin D deficiency results from decreased binding of the vitamin D receptor with its ligand on the vascular endothelium and that it may be immune-mediated via increased interferon 1 α. A possible sequence of events may be described as (1) angiotensin II converting enzyme-related initial endothelial injury followed by vitamin D receptor-related endothelial dysfunction, (2) endothelial lesions deteriorating to endothelialitis, coagulopathy and thrombosis, and (3) vascular damage exacerbating pulmonary pathology and making patients with vitamin D deficiency vulnerable to death.

Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy.

Great attention has been paid to endothelial dysfunction (ED) in coronavirus disease 2019 (COVID-19). There is growing evidence to suggest that the angiotensin converting enzyme 2 receptor (ACE2 receptor) is expressed on endothelial cells (ECs) in the lung, heart, kidney, and intestine, particularly in systemic vessels (small and large arteries, veins, venules, and capillaries). Upon viral infection of ECs by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), ECs become activated and dysfunctional. As a result of endothelial activation and ED, the levels of pro-inflammatory cytokines (interleukin -1, interleukin-6 (IL-6), and tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII are elevated. Higher levels of acute phase reactants (IL-6, C-reactive protein, and D-dimer) are also associated with SARS-CoV-2 infection. Therefore, it is reasonable to assume that ED contributes to COVID-19-associated vascular inflammation, particularly endotheliitis, in the lung, heart, and kidney, as well as COVID-19-associated coagulopathy, particularly pulmonary fibrinous microthrombi in the alveolar capillaries. Here we present an update on ED-relevant vasculopathy in COVID-19. Further research for ED in COVID-19 patients is warranted to understand therapeutic opportunities.

Inpatient Mortality According to Level of Respiratory Support Received for Severe Acute Respiratory Syndrome Coronavirus 2 (Coronavirus Disease 2019) Infection: A Prospective Multicenter Study.

OBJECTIVES: To describe patients according to the maximum degree of respiratory support received and report their inpatient mortality due to coronavirus disease 2019. DESIGN: Analysis of patients in the Coracle registry from February 22, 2020, to April 1, 2020. SETTING: Hospitals in the Piedmont, Lombardy, Tuscany, and Lazio regions of Italy. PATIENTS: Nine-hundred forty-eight patients hospitalized for coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 948 patients, 122 (12.87%) received invasive ventilation, 637 (67.19%) received supplemental oxygen only, and 189 (19.94%) received no respiratory support. The median (quartile 1-quartile 3) age was 65 years (54-76.59 yr), and there was evidence of differential respiratory treatment by decade of life (p = 0.0046); patients greater than 80 years old were generally not intubated. There were 606 men (63.9%) in this study, and they were more likely to receive respiratory support than women (p < 0.0001). The rate of in-hospital death for invasive ventilation recipients was 22.95%, 12.87% for supplemental oxygen recipients, and 7.41% for those who received neither (p = 0.0004). A sensitivity analysis of the 770 patients less than 80 years old revealed a lower, but similar mortality trend (18.02%, 8.10%, 5.23%; p = 0.0008) among the 14.42%, 65.71%, and 19.87% of patients treated with mechanical ventilation, supplemental oxygen only, or neither. Overall, invasive ventilation recipients who died were significantly older than those who survived (median age: 68.5 yr [60-81.36 yr] vs 62.5 yr [55.52-71 yr]; p = 0.0145). CONCLUSIONS: Among patients hospitalized for coronavirus disease 2019, 13% received mechanical ventilation, which was associated with a mortality rate of 23%.

Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers and outcomes in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: The use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in patients with coronavirus disease 2019 (COVID-19) given their interaction with the angiotensin-converting enzyme-2 (ACE-2) receptor remains controversial. . OBJECTIVE: To investigate the impact of ACEI/ARB on COVID-19 disease severity and mortality through a systematic review and meta-analysis. METHODS: We searched PubMed and CINAHL databases as well as pre-print servers for studies investigating usage of ACEIs/ARBs in patients with COVID-19 compared to a control group of COVID-19 patients without ACEI/ARB use. COVID-19 related severity of disease, and death were identified as end points. Pooled odds ratios (OR) and their 95% confidence intervals (CI) were calculated using random-effects model. RESULTS: 21 studies were included in the meta-analysis. For mortality with ACEI/ARB use, the pooled odds ratio was 1.29 [0.89-1.87] p = 0.18 with heterogeneity of 91%, while the pooled OR for COVID-19 severity was 0.94 [0.59-1.50] p = 0.81 with heterogeneity of 89% (Figure 2). In combining both mortality and severe disease outcomes, the pooled odds ratio was 1.09 [0.80-1.48] p = 0.58 but with heterogeneity of 92%. EXPERT OPINION: Even on pooled analysis of both un-adjusted data, adjusted data(studies with matched controls) and taking into account factors such as risk of bias of studies via meta regression and sensitivity analyses, the results hold true that ACEI/ARB use is not associated with COVID-19 disease severity or mortality. To look for any potential beneficial effects, randomized controlled trials are needed. CONCLUSION: use of ACEI/ARB was not associated with increased mortality or severe COVID-19.

Ventricular Fibrillation Storm in Coronavirus 2019.

Cardiac arrhythmia is a known manifestation of novel coronavirus 2019 (COVID-19) infection. Herein, we describe the clinical course of an otherwise healthy patient who experienced persistent ventricular tachycardia and fibrillation which is believed to be directly related to inflammation, as opposed to acute myocardial injury or medications that can prolong the QT interval.

Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection.

Approximately 9 months of the severe acute respiratory syndrome coronavius-2 (SARS-CoV-2 [COVID-19]) spreading across the globe has led to widespread COVID-19 acute hospitalizations and death. The rapidity and highly communicable nature of the SARS-CoV-2 outbreak has hampered the design and execution of definitive randomized, controlled trials of therapy outside of the clinic or hospital. In the absence of clinical trial results, physicians must use what has been learned about the pathophysiology of SARS-CoV-2 infection in determining early outpatient treatment of the illness with the aim of preventing hospitalization or death. This article outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic therapy, and 5) administration of oxygen, monitoring, and telemedicine. Future randomized trials testing the principles and agents discussed will undoubtedly refine and clarify their individual roles; however, we emphasize the immediate need for management guidance in the setting of widespread hospital resource consumption, morbidity, and mortality.