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Covid-19: Known risk factors fail to explain the increased risk of death among people from ethnic minorities

BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1873 (Published 11 May 2020) Cite this as: BMJ 2020;369:m1873

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African-Americans: Biological Factors and Elevated Risk for COVID-19

Dear Editor,

The U.S. Centers for Disease Control and Prevention (CDC) recently summarized preliminary evidence from New York City pointing to a substantially higher death rate (of 88% analyzed) from COVID-19 among Black/African American persons (92.3/100,000), Hispanic/Latino persons (74.3) versus White (45.2) and Asian (34.5) persons.[1]. While Black Americans represent only ~13% of the population in states reporting fatalities by race/ethnicity (~35% of total U.S. deaths), they account for ~34% of total COVID-19 deaths in those states.[2]. The differential death rate among Black vs. White persons has been related to economic, social and pre-existing health conditions but underlying biological factors have not been addressed. One important biological variable is the ethnic diversity in propensity for blood coagulation, the dysfunction of which can lead to arteriovenous thrombosis, a major cause of death among Chinese and Dutch patients with severe COVID-19.[3, 4].

German physician Rudolf Virchow (1821-1902), “father of modern pathology”, proposed that three factors contribute to thrombosis: hypercoagulability, hemodynamic changes (stasis, turbulence) and endothelial injury/dysfunction (Virchow’s triad). SARS-CoV-2 infection of the vascular endothelium, which regulates vascular tone and homeostasis, may promote vasoconstriction, inflammation, tissue oedema and a pro-coagulant state.[5]. The intrinsic coagulation pathway-kinin includes Factor FIX that is involved in the initiation and propagation phases of thrombin generation. A prospective study of U.S.-wide Black and White adults aged ≥ 45 years showed that higher FIX antigen levels in Blacks were associated with an increased risk of incident coronary heart disease.[6]. African-Americans also have diminished kallikrein and potassium excretion.[7].

Vitamin status also appears to be an important biological variable in COVID-19 risk and outcome. For example, population genetic variability exists for vitamin K epoxide reductase (VKOR); polymorphisms in the VKORC1 (2,3-epoxide reductase complex subunit 1), which participates in thrombosis, has a greater frequency in Japanese (89.1%) than Caucasians (42.2%) and African-Americans (8.6%).[8]. Additionally, low vitamin D status among U.S. Black men and women over 65 has been raised as a potential risk factor for thrombosis among elderly subjects with COVID-19.[9]. In their posted preprint, Daneshkhah and colleagues propose that vitamin D deficiency in the elderly may promote aberrant responses of the innate immune system that increase the SARS-CoV-2 load; this in turn over-activates the adaptive immune system and triggers the cytokine storm seen in severe COVID-19 cases. The potentially fatal cytokine storm brings complications such as Acute Respiratory Depression Syndrome, increased effects of pneumonia, acute kidney failure, acute heart failure, and rhabdomyolysis.[10]. Plasma levels of vitamin B1, vitamin C and zinc are also involved in haemostasis and thrombosis.

Cerebrovascular disease, in particular large-vessel ischemic strokes, and less frequently cerebral venous thrombosis, intracerebral hemorrhage and subarachnoid hemorrhage, occur as part of a thrombotic state apparently induced by attachment of SARS-CoV-2 to endothelial plasma membrane angiotensin-converting enzyme-2 receptors. This results in widespread endotheliitis, coagulopathy, thromboses and stroke.[11]. Stroke in African-ancestry populations is highly heritable and influenced by genetic determinants underlying cardiovascular risk factors. In the United Kingdom, Black persons were 42% more likely than White persons to be diagnosed with dementia.[12, 13]. Serum amyloid A, an acute-phase cytokine inflammatory-marker protein also produced in the brain where it co-localizes with senile plaques in patients with Alzheimer disease,[14] is markedly elevated in severe COVID-19.[15].

In conclusion, innate biological susceptibilities, as well as socioeconomic factors, preexisting health conditions and access to healthcare, among other risk factors, may help to explain higher rates of COVID-19 infection and death of Black persons.

References
1. CDC. COVID-19 in racial and minority ethnic groups. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/racial-... [Accessed May 4, 2020]
2. Cooper LA. Maps & trends: Racial data transparency. States that have released breakdowns of Covid-19 by race. Coronavirus Resource Center, Johns Hopkins University, Baltimore, MD. https://coronavirus.jhu.edu/data/racial-data-transparency [Accessed May 4, 2020].
3. Song JC, Wang G, Zhang W et al. People’s Liberation Army Professional Committee of Critical Care Medicine, Chinese Society on Thrombosis and Haemostasis. Chinese expert
consensus on diagnosis and treatment of coagulation dysfunction in COVID-19. Mil Med Res 2020;7:19. doi: 10.1186/s40779-020-00247-7.
4. Klok FA, Kruip MJHA, van der Meer NJM et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; pii: S0049-3848(20)30120-1. doi: 10.1016/j.thromres.2020.04.013.
5. Varga Z, Flammer AJ, Steiger P et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417-8. doi: 10.1016/S0140-6736(20)30937-5.
6. Olson NC, Cushman M, Judd SE et al. Associations of coagulation factors IX and XI levels with incident coronary heart disease and ischemic stroke: the REGARDS study. J Thromb Haemost 2017;15:1086-94. doi: 10.1111/jth.13698.
7. Song CK, Martinez JA, Kailasam MT et al. Renal kallikrein excretion: Role of ethnicity, gender, environment, and genetic risk of hypertension. J Hum Hypertens. 2000;14:461-8. doi: 10.1038/sj.jhh.10001047.
8. Takahashi H, Wilkinson GR, Nutescu EA et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 2006;16:101-10.
9. Brown RA. Preventing a covid-19 pandemic. BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m810
10. Daneshkhah A, Eshein A, Subramanian H, Roy HK, Backman V. The role of vitamin D in suppressing cytokine Storm in COVID-19 patients and associated mortality. medRxiv preprint doi: https://doi.org/10.1101/2020.04.08.20058578
11. Román GC, Spencer PS, Reis J, et al., for the WFN Environmental Neurology Group. J Neurol Sci, in press.
12. Traylor M, Rutten-Jacobs L, Curtis C et al. Genetics of stroke in a UK African ancestry case-control study: South London Ethnicity and Stroke Study. Neurol Genet 2017;3:e142. doi: 10.1212/NXG.0000000000000142.
13. Shiekh SI, Forbes H, Mathur R et al. Ethnicity and risk of diagnosed dementia after stroke: a cohort study using the Clinical Practice Research Datalink. J Epidemiol Community Health 2020;74:114-9. doi: 10.1136/jech-2019-212825.
14. Yu Y, Liu J, Li SQ, Peng L, Ye RD. Serum amyloid a differentially activates microglia and astrocytes via the PI3K pathway. J Alzheimers Dis 2014;38:133-44. doi: 10.3233/JAD-130818.
15. Li H, Xiang X, Ren H et al. Serum Amyloid A is a biomarker of severe Coronavirus Disease and poor prognosis. J Infect Dis 2020 Apr 8. pii: S0163-4453(20)30162-6. doi: 10.1016/j.jinf.2020.03.035.
marker protein that is also produced in the brain, where it co-localizes with senile plaques in patients with Alzheimer disease,[14] is markedly elevated in severe COVID-19.[15].

Competing interests: No competing interests

11 May 2020
Valerie S. Palmer
Faculty of Neurology
Peter S. Spencer
Oregon Health & Science University, Portland, Oregon 97239, USA
Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239