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      The Fire This Time: The Stress of Racism, Inflammation and COVID-19

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      a , * , b
      Brain, Behavior, and Immunity
      Elsevier Inc.

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          Abstract

          1 African Americans, Social Determinants of Health and COVID-19 It is said that crisis reveals character. The COVID-19 pandemic has revealed the inequitable character of the U.S. health care system by the alarming death rates among African Americans with COVID-19. Nationwide, African Americans represent a third of hospitalized COVID-19 patients but make up only 13% of the U.S. population. In Chicago, one of the nation’s hotspots, African American make up 42% of the cases and 56% of the deaths from the virus (Chicago COVID-19 Update. https://www.chicago.gov/city/en/sites/covid-19/home/latest-data.html. Accessed April 26, 2020). These racial disparities have been noted in other countries as well. A recent study from the United Kingdom demonstrated that Black participants had a 4-fold increase in COVID-19 hospitalizations compared to their White participants, even after controlling for several economic and physiological factors (Lassale et al., 2020). There are several pathways that contribute to racial disparities in COVID-19 cases and death. First, we must consider biological underpinnings that are specific to COVID-19. Angiotensin-Converting Enzyme 2 (ACE2) is the entry receptor utilized by COVID-19 and is thought to negatively regulate the activated renin-angiotensin system by diverting the generation of vasoconstrictor angiotensin II (AngII) towards the inactive Ang 1–9 and vasodilatatory Ang 1–7 peptides. A few studies have found racial differences in ACE2 activity, showing African Americans produce higher levels of AngII and demonstrate lower ACE2 activity (Brewster and Seedat, 2013). Studies have shown that downregulation of ACE2 expression is involved in lung pathology after SARS-CoV infection and elevations in AngII have been directly related to COVID-19 severity (Liu et al., 2020). Hence, dysregulation of the renin-angiotensin system may place African Americans at disproportionate risk for severe COVID-19 outcomes. The second, and perhaps most critical factor, relates to health disparities. African Americans disproportionally account for >45% of vascular-related diseases and are 37% more likely to develop lung cancer than whites, despite lower exposure to cigarette smoke. Social determinant factors like economic stability, education, and the environment directly impact issues related to access and quality of health care, which fuel health disparities. Furthermore, there is evidence of medical bias in the testing and treatment of African-American with COVID-19 (COVID-19 and Minority Health Access: Rubix Life Sciences, 2020). We must ask ourselves, “Why do these social inequities persist despite decades of scientific evidence showing its damaging effects on health?” We believe the answer lies in a close examination of structural forms of racism and discrimination towards African Americans. Historically, African Americans have been a target group for racism and discrimination which has created a deep mistrust for societal systems - often undermined as “paranoia.” Specific to COVID-19, African Americans are overrepresented in “essential” jobs, therefore, employment may interfere with the ability to stay at home and social distance. We must not forget that stay at home orders and social distancing carries an assumption of socioeconomic privilege (I.e., the ability to work from home and transition from in-person communications to online platforms). 1.1 Biological consequences of the stress of racism COVID-19 has brought these longstanding issues to light in a stark way. What is less appreciated are the biological consequences of structural racism and discrimination. Increasing evidence support the effects of racial discrimination on biological function. First, altered immune function, hypothalamic-pituitary axis (HPA) dysfunction, and metabolic changes secondary to stress can contribute to medical co-morbidities such as type 2 diabetes, hypertension and asthma, all of which increase COVID-19 risk. Everyday discrimination is a stressor that has been linked to poor health, inflammation, and premature cellular aging (Chae et al., 2020). Hence, discrimination experiences may also explain why African Americans are at a disproportionately higher risk for poor medical (e.g., cardiovascular disease, metabolic, hypertension) and psychiatric outcomes (e.g., depression, anxiety). Disparities in health outcomes may also reflect dysfunctions in the body’s innate (immediate) and adaptive (prolonged) immune responses, which are evolutionarily designed to defend against and prevent the spread of pathogens. During initial exposure to a new pathogen, Toll-like receptors play a critical role in innate and inflammatory immune responses. Dysfunctional alterations in the adaptive immune response may promote a “cytokine storm”, whereby the immune system begins to attack its own cells and tissues (Mehta et al., 2020) which has been seen in severe cases of COVID-19. The field of social genomics has uncovered how certain marginalized groups demonstrate abnormal patterns of gene expression in genes responsible for innate immunity, termed the Conserved Transcriptional Response to Adversity (CTRA (Cole, 2014). CTRA refers to a common pattern of transcriptional alterations that is activated by chronic low-grade activation of the sympathetic nervous system (SNS). The CTRA profile is characterized by increased expression of genes involved in inflammation, and decreased expression of genes involved in innate antiviral responses and genes encoding specific isotypes of antibodies (IgG in particular). Experiences of racial discrimination have been found to explain more than 50% of the Black-White differences in CTRA, particularly in genes that promote inflammation (Thames et al., 2019). Together, these studies provide a potential pathway as to how racism and discrimination alter host innate immunity to promote abnormal inflammatory responses. 1.2 Neuropsychiatric sequelae of COVID-19 The neuropsychiatric sequelae of COVID-19 have both direct and indirect pathways. The direct pathway relates to the stress-induced inflammatory factors (as described above) that may increase risk for encephalopathies, depression, anxiety, and trauma-related disorders (Troyer et al., 2020). It is hypothesized that these neuropsychiatric manifestations could result from the virus-induced “cytokine storm”. The indirect pathway relates to measures to address the pandemic like social distancing as well as the economic toll of COVID-19. There is growing concern that these indirect consequences of COVID-19 may contribute to isolation, anxiety, depression, and increased rates of suicide (Gunnell et al., 2020). As a result of these direct and indirect pathways, African Americans are specifically vulnerable to the neuropsychiatric consequences of COVID-19. 2 Conclusions The crisis generated by the COVID-19 pandemic has forced us to confront issues of inequality and health disparities. While considerable efforts are being made to “flatten the curve”, it does not negate the damage that has already been done, particularly in the African American community. While the virus is not thought to target specific racial or ethnic groups, we cannot ignore that African Americans have been disproportionately impacted. As we think about getting past this crisis and getting back to “normal”, the pandemic provides an opportunity to improve our health system to reduce disparities. In sum, understanding the key biological and psychosocial contributors to the ravishes of COVID-19 in African Americans highlights the need for more vigilance, attention, and efforts to improve health for all. Contributor’s Statement: Both authors (OA and AT) contributed to the writing of this manuscript. Disclosures: Dr. Ajilore is the co-founder of KeyWise, Inc and serves on the advisory board of Blueprint Health and Embodied Labs

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          Most cited references8

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          COVID-19: consider cytokine storm syndromes and immunosuppression

          As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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            Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

            The outbreak of the 2019-nCoV infection began in December 2019 in Wuhan, Hubei province, and rapidly spread to many provinces in China as well as other countries. Here we report the epidemiological, clinical, laboratory, and radiological characteristics, as well as potential biomarkers for predicting disease severity in 2019-nCoV-infected patients in Shenzhen, China. All 12 cases of the 2019-nCoV-infected patients developed pneumonia and half of them developed acute respiratory distress syndrome (ARDS). The most common laboratory abnormalities were hypoalbuminemia, lymphopenia, decreased percentage of lymphocytes (LYM) and neutrophils (NEU), elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased CD8 count. The viral load of 2019-nCoV detected from patient respiratory tracts was positively linked to lung disease severity. ALB, LYM, LYM (%), LDH, NEU (%), and CRP were highly correlated to the acute lung injury. Age, viral load, lung injury score, and blood biochemistry indexes, albumin (ALB), CRP, LDH, LYM (%), LYM, and NEU (%), may be predictors of disease severity. Moreover, the Angiotensin II level in the plasma sample from 2019-nCoV infected patients was markedly elevated and linearly associated to viral load and lung injury. Our results suggest a number of potential diagnosis biomarkers and angiotensin receptor blocker (ARB) drugs for potential repurposing treatment of 2019-nCoV infection. Electronic Supplementary Material Supplementary material is available for this article at 10.1007/s11427-020-1643-8 and is accessible for authorized users.
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              Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms ☆

              Highlights • The COVID-19 pandemic is a significant source of psychological distress globally. • The novel coronavirus and host immunologic response may also directly affect brain and behavior. • Acute and delayed neuropsychiatric sequelae have been associated with past viral pandemics. • Prospective monitoring of COVID-19 patients is needed to determine neuropsychiatric outcomes. • A psychoneuroimmunology perspective will aid in promoting post-pandemic public mental health.
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                Author and article information

                Contributors
                Journal
                Brain Behav Immun
                Brain Behav. Immun
                Brain, Behavior, and Immunity
                Elsevier Inc.
                0889-1591
                1090-2139
                4 June 2020
                4 June 2020
                Affiliations
                [a ]Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
                [b ]Departments of Psychology and Psychiatry, University of Southern California, Los Angeles, CA, USA
                Author notes
                [* ]Corresponding Author at: 1601 W. Taylor Street, Chicago, IL 60612, United States oajilore@ 123456uic.edu
                Article
                S0889-1591(20)31042-4
                10.1016/j.bbi.2020.06.003
                7272146
                32505712
                b7b456bf-33d6-430d-809f-a68004411d9e
                © 2020 Elsevier Inc. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 21 May 2020
                : 29 May 2020
                : 2 June 2020
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                Neurosciences
                Neurosciences

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