The disproportionate number of COVID-19 fatalities among African Americans is being widely reported across America and achieving a better understanding of why is of the utmost importance and urgency. Social scientists have attempted to explain the discrepancy by occupational exposures to the service industries, crowded residential spaces, and a greater incidence of morbidity second to poor healthcare access. The social aspect of this disease should not be trivialized and undoubtedly contributes substantially to mortality. In fact, while I plan to make the case for a biological contribution to disease burden, it is more than likely that this biological mechanism is in fact driven by social disparity, and that should not be lost on us.
But social change takes decades, while hundreds of African Americans will die today, tomorrow, and in weeks to come. I believe that I not only have a plausible theory as to why this disparity exists, but also a possible solution.
Why do some medical conditions put people more at risk for severe COVID-19 disease and death? Some explanations are somewhat self-explanatory. It makes sense, for instance, that a person with chronic lung disease would not fair well with a condition that floods the lungs with fluid. Hypertension, on the other hand, is a more curious independent risk factor, a condition that notably plagues African Americans at a much higher incidence than Caucasians.
While the pathophysiology of hypertension is complex and multifaceted, there are notable racial differences. In the context of COVID-19, the most suspicious difference is a comparative deficiency of L-arginine and subsequently nitric oxide (NO). In this lies a potential explanation for the COVID-19 race disparity.
NO is a gas synthesized by our cells and has multiple roles, but perhaps is best known for vascular dilation. In short, NO facilitates relaxation of vascular smooth muscle allowing vessel dilation and increased blood flow.
This on its own has potential implications in acute respiratory distress syndrome (ARDS), a condition that results from severe COVID-19 infection. By improving blood flow across the entire lung, this theoretically results in improved gas exchange and oxygenation of the blood. In fact, there is research that inhaled NO improved oxygenation and other clinical outcomes in SARS-1 patients, and current research in COVID-19 coronavirus (SARS-CoV-2) supports this previously demonstrated efficacy.
Additionally, abnormal blood clotting is an increasingly recognized complication of this disease, both systemically and within the pulmonary circulation. In fact, one of the greatest predictors of death is a serum blood test that indicates elevated clotting activity. Most recently, some physicians have suggested that small clots within the lungs are central to pathogenesis and have administered clot busting drugs known as thrombolytics which abruptly improve oxygenation, albeit transiently, as the medication effect weans and the predisposition to clot formation persists. NO inhibits clot formation, and deficiency may contribute to a prothrombotic state. In fact, it has been shown that inhaled NO decreases the propensity of clotting in ARDS.
However, perhaps the most convincing role of nitric oxide in this disease is its antiviral properties. SARS-CoV-2 infects cells by attaching to a receptor on the lining of the airways called angiotensin-converting enzyme 2 (ACE2). This is the same mechanism by which SAR-1 infects cells. NO specifically alters a surface protein on SARS-1, known as the spike protein, such that it cannot attach to the ACE2 receptor. This results in blocking viral entry into the cell as well as the subsequent replication of the virus. Since SARS-CoV-2 shares the same mechanism of cell entry, we can relatively confidently assume that NO would have a similar effect regarding this novel virus.
Knowing that NO deficiency is common in African Americans and that this population is disproportionately dying from an infection that can be blocked by this gas, augmenting NO seems like a reasonable therapeutic target. While NO is being used as an inhaled gas via mechanical ventilation, this is only suitable for someone ill enough to require mechanical ventilation.
A better way to increase nitric oxide in the minimally ill or even uninfected is to augment the body's ability to create it. There are many pharmacologic ways to do this; however, potentially the most effective, cheapest, and lowest risk is to supplement with the precursor amino-acids L-arginine and L-citrulline. We already know these nutritional supplements result in this very effect and that there seems to be a more potent effect of supplementation on NO production in L-arginine-deficient African Americans.
Therefore, a reasonable action is to expedite clinical trials to further investigate this theory. At a minimum, we need to start a conversation to improve our understanding of the role of nitric oxide deficiency as a risk factor for disease severity. It is my strong belief that augmenting NO via L-arginine and L-citrulline not only has potential for treatment and reducing progression to severe illness, but given the safety profile, it may be most valuable as a preventative measure.
It could save many lives at a minimal cost.
Jason Kidde, MS, MPAS, is a physician assistant at University of Utah Health in Salt Lake City.