The COVID-19 Mortality Puzzle: A Single Explanation for Why Men, Elders, People of Color, and Hypertensives are Dying from Coronavirus

Abstract

Oxidative stress, particularly through excess endogenous NADPH-oxidase production of oxygen free-radicals, is proposed here as the single unifying framework for explaining the seemingly puzzling range of risk factors for severe coronavirus (SARS-CoV-2) infection including aging, male gender, African-American race, cardiovascular disease, obesity, and diabetes. Evidence is presented that death rate as a function of age better resembles the near-exponential rise seen in cancer, where oxidative stress is high, rather than the historical W or U-shaped functions of pandemic or seasonal flu. In addition, consideration of more than 10,000 CDC and Montgomery County, PA publicly available cases suggested a deviation from an exponential rise in the oldest-old, consistent with lower oxidative stress levels reported in that group. Gender analyses unexpectedly found male-to-female risk of mortality to be an inverted U-shaped function peaking at nearly 2.5 times from age 30 to 50 and may reverse to half the female risk at the oldest ages, providing a good fit to known oxidative stress gender differences across the lifespan. Race data were consistent with higher mortality from COVID-19 and higher oxidative stress levels in African Americans. It is argued pre-existing conditions that increase risk all share high oxidative stress levels while, intriguingly, the possibly protective Inflammatory Bowel Disease and Lupus have low levels of NADPH oxidase-derived oxygen free radicals. It is further argued that oxidative stress is not simply a useful construct but its ability to explain differences in coronavirus severity stems from the known unique adaptations in bats, where the virus co-evolved, to accommodate flight which generates large amounts of oxygen free radicals. Finally, strategies for prevention and treatment that follow from the theory are briefly covered including N-acetyl cysteine in older men to restore glutathione levels to more youthful values and especially exciting, pursuing the inhibition of NADPH oxidases not only with well-known melatonin but also with less known compounds such as the naturally occurring apocynin, which is also inexpensive and readily available.