The United States is in an acceleration phase of the COVID-19 pandemic. Currently there is no known effective therapy or vaccine for treatment of SARS-CoV-2, highlighting urgency around identifying effective therapies. Objective: The purpose of this study was to evaluate the role of hydroxychloroquine therapy alone and in combination with azithromycin in hospitalized patients positive for COVID-19. Design: Multi-center retrospective observational study. Setting: The Henry Ford Health System (HFHS) in Southeast Michigan: large six hospital integrated health system; the largest of hospitals is an 802-bed quaternary academic teaching hospital in urban Detroit, Michigan. Participants: Consecutive patients hospitalized with a COVID-related admission in the health system from March 10, 2020 to May 2, 2020 were included. Only the first admission was included for patients with multiple admissions. All patients evaluated were 18 years of age and older and were treated as inpatients for at least 48 h unless expired within 24 h. Exposure: Receipt of hydroxychloroquine alone, hydroxychloroquine in combination with azithromycin, azithromycin alone, or neither. Main outcome: The primary outcome was in-hospital mortality. Results: Of 2,541 patients, with a median total hospitalization time of 6 days (IQR: 4-10 days), median age was 64 years (IQR:53-76 years), 51% male, 56% African American, with median time to follow-up of 28.5 days (IQR:3-53). Overall in-hospital mortality was 18.1% (95% CI:16.6%-19.7%); by treatment: hydroxychloroquine + azithromycin, 157/783 (20.1% [95% CI: 17.3%-23.0%]), hydroxychloroquine alone, 162/1202 (13.5% [95% CI: 11.6%-15.5%]), azithromycin alone, 33/147 (22.4% [95% CI: 16.0%-30.1%]), and neither drug, 108/409 (26.4% [95% CI: 22.2%-31.0%]). Primary cause of mortality was respiratory failure (88%); no patient had documented torsades de pointes. From Cox regression modeling, predictors of mortality were age>65 years (HR:2.6 [95% CI:1.9-3.3]), white race (HR:1.7 [95% CI:1.4-2.1]), CKD (HR:1.7 [95%CI:1.4-2.1]), reduced O2 saturation level on admission (HR:1.5 [95%CI:1.1-2.1]), and ventilator use during admission (HR: 2.2 [95%CI:1.4-3.3]). Hydroxychloroquine provided a 66% hazard ratio reduction, and hydroxychloroquine + azithromycin 71% compared to neither treatment (p < 0.001). Conclusions and relevance: In this multi-hospital assessment, when controlling for COVID-19 risk factors, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality. Prospective trials are needed to examine this impact.

Background There is no proven antiviral or immunomodulatory therapy for COVID-19. The disease progression associated with the pro-inflammatory host response prompted us to examine the role of early corticosteroid therapy in patients with moderate to severe COVID-19. Methods We conducted a single pre-test, single post-test quasi-experiment in a multi-center health system in Michigan from March 12 to March 27, 2020. Adult patients with confirmed moderate to severe COVID were included. A protocol was implemented on March 20, 2020 using early, short-course, methylprednisolone 0.5 to 1 mg/kg/day divided in 2 intravenous doses for 3 days. Outcomes of standard of care (SOC) and early corticosteroid groups were evaluated, with a primary composite endpoint of escalation of care from ward to ICU, new requirement for mechanical ventilation, and mortality. All patients had at least 14 days of follow-up. Results We analyzed 213 eligible subjects, 81 (38%) and 132 (62%) in SOC and early corticosteroid groups, respectively.The composite endpoint occurred at a significantly lower rate in the early corticosteroid group (34.9% vs. 54.3%, p=0.005). This treatment effect was observed within each individual component of the composite endpoint. Significant reduction in median hospital length of stay was also observed in the early corticosteroid group (8 vs. 5 days, p &lt; 0.001). Multivariate regression analysis demonstrated an independent reduction in the composite endpoint at 14-days controlling for other factors (aOR: 0.41; 95% CI [0.22 – 0.77]). Conclusion An early short course of methylprednisolone in patients with moderate to severe COVID-19 reduced escalation of care and improved clinical outcomes.

Consumption of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can mitigate the progression of diseases in which oxidative stress represents a common underlying biochemical process. Nrf2-regulated gene expression regulates detoxification of reactive oxygen species. EPA and DHA were subjected to an in vitro free radical oxidation process that models in vivo conditions. Oxidized n-3 fatty acids reacted directly with the negative regulator of Nrf2, Keap1, initiating Keap1 dissociation with Cullin3, thereby inducing Nrf2-directed gene expression. Liquid chromatography-tandem mass spectrometry analyses of oxidized EPA demonstrated the presence of novel cyclopentenone-containing molecules termed J 3 -isoprostanes in vitro and in vivo and were shown to induce Nrf2-directed gene expression. These experiments provide a biochemical basis for the hypothesis that formation of J-ring compounds generated from oxidation of EPA and DHA in vivo can reach concentrations high enough to induce Nrf2-based cellular defense systems.Eicosapentaenoic acid (EPA, C20:5n-3) 5 and docosahexaenoic acid (DHA, C22:6n-3) are two major components of fish oil. Epidemiological studies and randomized controlled trials have demonstrated that n-3 fatty acid supplementation can reduce sudden cardiac death, nonfatal stroke, and decrease progression of arteriosclerosis (1-3). Dietary supplementation with fish oil also shows promise for suppressing progression of neurodegenerative diseases (4), neuropsychiatric disorders (5), human immunodeficiency virus (6), and diseases of the retina (7). Thus, identifying the molecular mechanism(s) responsible for n-3 fatty acid mitigation of these diverse diseases represents an important and intriguing question.Oxidative stress is a common factor in the etiology of the diseases impacted by DHA and EPA (1, 8 -17). These n-3 fatty acids are very susceptible to free radical oxidation, exceeding that of arachidonic acid (AA) (18 -20). Yet, recent studies have shown that EPA and DHA supplementation reduced urinary F 2 -isoprotane levels, a marker for oxidative stress, as well as enhanced cellular antioxidant defense systems (21-24). Although a reduction of F 2 -isoprostane levels can be attributed, in part, to a decrease in membrane AA content (20,25), the relationship between EPA/ DHA oxidation versus EPA/DHA-mediated induction of antioxidant responses is not well understood.Non-enzymatic free-radical peroxidation of AA results in the formation of multiple stereoisomers of prostaglandin H 2 -like bicyclic endoperoxides that can undergo thiol-mediated reduction to form prostaglandin-like compounds termed F 2 -isoprostanes (F 2 -IsoPs) or rearrangement and reduction to form E 2 -IsoPs, D 2 -IsoPs, and isothromboxanes. E 2 /D 2 -IsoPs can then dehydrate to highly reactive A 2 /J 2 -isoprostanes containing cyclopentenone rings. These compounds readily adduct thiol groups on proteins and have been shown to induce Nrf2/ ARE-directed gene expression (26).NF-E2-related factor 2, Nrf2, is a master transcription factor ...

Background: COVID-19 disease has spread globally and was declared a pandemic on March 11, 2020, by the World Health Organization. On March 10, the State of Michigan confirmed its first 2 cases of COVID-19, and the number of confirmed cases has reached 47,182 as of May 11, 2020, with 4555 deaths. Setting: Currently, little is known if patients living with HIV (PLWH) are at a higher risk of severe COVID-19 or if their antiretrovirals are protective. This study presents epidemiologic and clinical features of COVID-19 infected PLWH in Detroit, Michigan. Methods: This is a case series that included 14 PLWH with laboratory-confirmed COVID-19 infection who were evaluated at Henry Ford Hospital in Detroit, Michigan, between March 20, 2020, and April 30, 2020. Results: Fourteen PLWH were diagnosed with COVID-19. Twelve patients were men and 2 were women; 13 patients were virally suppressed. Eight patients were hospitalized, and 6 patients were told to self-quarantine at home after their diagnoses. Three patients who were admitted expired during their hospital stay. No patient required bilevel positive airway pressure or nebulizer use in the emergency department, and none developed acute respiratory distress syndrome, pulmonary embolism, deep venous thrombosis, or a cytokine storm while on therapy for COVID-19. Conclusion: Although the clinical spectrum of COVID-19 among PLWH cannot be fully ascertained by this report, it adds to the data that suggest that HIV-positive patients with SARS-CoV-2 infection are not at a greater risk of severe disease or death as compared to HIV-negative patients.