Everyone has the potential to catch the SARS-CoV-2 virus, which causes COVID-19.1 You can significantly affect your risk of infection and severity of disease by taking simple steps. Symptoms for COVID-19 can range from mild to devastating.

There are factors that increase the risk a person may experience severe disease. These include underlying medical conditions such as obesity, heart disease, Type 2 diabetes and chronic obstructive pulmonary disease.2

In one evaluation of COVID-19 patients from six hospitals in Atlanta, researchers found independent factors that raised the risk of hospitalization included being male, smoking, having Type 2 diabetes, being of advanced age and being obese.3

The data also showed that African-Americans had a higher incidence of hospitalization, which correlates with lower levels of vitamin D, a significant risk factor for COVID-19 severity.4 In one estimation published just months before the announcement of COVID-19, researchers found that 40% of U.S. adults are deficient in the vitamin. However, that number rose to 76% for black Americans.5

There are also factors that may reduce your risk of severe disease. These can include maintaining your vitamin D level at 60 ng/mL to 80 ng/mL, addressing any underlying medical conditions, getting plenty of quality sleep, exercising and staying hydrated.

Clotting Complications With COVID-19 Raises Risk of Severity

James DiNicolantonio, Pharm.D, and Mark McCarty published a follow-up to a paper they released February 12, 2020. DiNicolantonio is a cardiovascular research scientist;6 McCarty is a biomedical theoretician and an applied nutritionist.7

In the first article, published in Progress in Cardiovascular Diseases, they made an argument for specific nutraceuticals that may provide relief for those infected with COVID-19.8,9 The second paper was recently published in Open Heart BMJ.10 In it, proposed a pathway that may result in severe disease.

The essay, which they clearly expressed as a hypothesis they believed to be credible, was intended to stimulate conversation and propose studies of the interactions between the virus and vascular endothelial cells.

The basis of the proposal focused on the high rate of clotting complications in those with severe COVID-19. DiNicolantonio and McCarty believe the pathway seems to reflect infection of the vascular endothelial cells. These cells have a high expression of ACE2 protein, which the SARS-CoV-2 virus uses to invade.

Patients with severe COVID-19 demonstrate hypercoagulability, which leads to acute respiratory failure. In one study, patients who were admitted to Padova University Hospital in Italy for acute respiratory failure showed “markedly hypercoagulable thromboelastometry profiles.” The researchers concluded:11

“In conclusion, COVID-19 patients with acute respiratory failure present a severe hypercoagulability rather than consumptive coagulopathy. Fibrin formation and polymerization may predispose to thrombosis and correlate with a worse outcome.”

There is some evidence that infection of the endothelial cells by SARS-CoV-2 virus leads to cell injury, which plays a role in organ failure.12

Pathogenic Role of NADPH

According to DiNicolantonio and McCarty, “It has been suggested that the thrombotic diathesis associated with COVID-19 reflects an endotheliopathy induced by viral infection of endothelial cells.”13

He proposes the clotting complications in a COVID-19 infection may be triggered when infected cells use the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) signaling pathway. That’s a mouthful to read, but NADPH is a key factor in the production of reactive oxygen species (ROS) produced during oxygen metabolism.14

It’s also an active communication component during viral and bacterial infections. The key takeaway here is that intracellular buildup of reactive oxygen species may inhibit viral replication. However, an excess amount increases cellular stress, which may lead to cell death.

Before SARS-CoV-2, researchers had demonstrated how some RNA viruses activate NADPH oxidase.15 COVID-19 is also a single strand RNA virus with intracellular uptake. DiNicolantonio and McCarty hypothesized that after being incorporated into endosomes in the endothelial cells, SARS-CoV-2 could also activate NADPH.

This would result in an increased local production of superoxide and hydrogen peroxide. Superoxide is a reactive oxygen species in which an electron is added to an oxygen molecule. The addition of another electron results in hydrogen peroxide.

As I’ve written before, superoxide plays a crucial role in the oxidative stress that occurs in chronic illnesses identified as comorbidities for COVID-19, such as obesity, heart disease and diabetes.

Pulmonologist Dr. Roger Seheult from MedCram.com hypothesizes that when SARS-CoV-2 attaches to and reduces an ACE2 receptor, it increases the amount of superoxide produced, which in turn causes oxidative stress leading to endothelial cell dysfunction and thrombosis.16

Selenium May Reduce Oxidative Stress and Cytokine Storm

DiNicolantonio and McCarty wrote that it was difficult to locate clinical studies measuring biomarkers of oxidative stress in patients with SARS-CoV-2. However, they noted that “provinces of China where soil selenium is deficient is compatible with the view that oxidant stress plays a key pathogenic role in this syndrome, and selenium is required for function of multiple antioxidant enzymes, including glutathione peroxidases and thioredoxin reductases.”17

DiNicolantonio suggests that hydroxychloroquine (HCQ), which is commonly used for systemic lupus erythematosus, may help reduce the clotting risk with COVID-19 as it does with systemic lupus erythematosus. He postulates:18

“… that HCQ can likewise prevent endosomal NADPH oxidase activation in SARS-CoV-2-exposed endothelial cells, thereby reducing risk for the thrombotic complications associated with COVID-19 infection.

This is of particular interest in light of the ability of HCQ to inhibit SARS-CoV-2 in vitro, and of preliminary evidence that administration of HCQ early in the course of COVID-19 may improve therapeutic outcomes, likely by slowing cell-to-cell spread of the virus.”

A potential nutraceutical with a powerful effect on reducing NADPH is spirulina, which he writes may explain the effect on reducing inflammation in animals when administered by mouth:

“In addition, phycocyanobilin (PCB), a biliverdin metabolite prominently expressed as a light-absorbing chromophore in cyanobacteria (such as spirulina) and many blue-green algae, has been found to mimic the ability of its chemical relative unconjugated bilirubin to inhibit NADPH oxidase complexes.”

Others have contemplated that spirulina may also support the type 1 interferon response and thus lower the potential for a cytokine storm, which is the hallmark symptom of severe COVID-19. Raising levels of glycine may also help suppress NADPH. Glycine may also help control thrombotic complications as it has a direct effect on platelets.

The authors hypothesize that using glutathione may help mediate the expression of enzymes that reverse cysteine oxidation. The expectation would be that this reaction would counteract the hydrogen peroxide signaling. The benefits could also be achieved using sulforaphane, lipoic acid or ferulic acid plus N-acetylcysteine (NAC):

“Measures that quell endothelial oxidative stress while supporting effective eNOS activity might not only help to control the thrombotic complications of COVID-19, but also be expected to blunt the exuberant influx of neutrophils that promote respiratory distress in this syndrome.”

Nutraceutical Therapeutic Interventions Lower Severity

The biochemical reactions leading the authors to these conclusions can get a little confusing. For a quick primer, see “Potential Roles of NAC and Glutathione in COVID-19 Treatment.” In that article, I go on to explain how NAC has antiviral properties and how it can help with acute respiratory distress syndrome. This is a serious complication associated with lung injury.

I also list some studies that have shown how NAC is beneficial to the treatment of lung-related problems and how it can protect against blood clots and strokes. Each of these factors play a significant role in the treatment of COVID-19.

DiNicolantonio and McCarty give specific recommendations for supplements that may help reduce thrombotic effects and subsequently reduce the severity of disease. These include:

Molecular Hydrogen — This is one of the absolute best strategies to improve pathology in diseases like COVID-19 as it selectively decreases oxidative stress if it is needed. One of the routes is by inhibiting NOX which subsequently decreases NADPH consumption thus increase NADPH.

Spirulina — This is a form of blue-green algae that grows in freshwater and saltwater. It’s a simple, one-celled organism that is technically a form of cyanobacteria that offers a number of health benefits.

Spirulina may help fight inflammation, provide allergy relief, enhance brain health and control high blood pressure. It comes in capsules, tablets, powders and flakes. DiNicolantonio recommends 15 g (rounded tablespoon of powder), one time per day.

Glycine powder — DiNicolantonio and McCarty write that “Supplemental glycine … has been found to exert anti-inflammatory, immunomodulatory, cytoprotective, platelet-stabilizing and antiangiogenic effects in rodent studies that may be of clinical relevance.”19

The powder is “inexpensive, highly soluble and has a pleasant sweet flavor”20 DiNicolantonio recommends taking 5 g, two to three times per day. You can use it as a healthy sweetener in tea or coffee.

Lipoic acid — This is a naturally occurring compound and a direct antioxidant. Some evidence suggests it can help with glucose utilization and IV administration may help reduce diabetic peripheral neuropathy.21 He recommends taking 600 mg, two to three times per day.

Broccoli sprout powder — This delivers sulforaphane, a compound that augments glutathione.22 DiNicolantonio recommends 5 g, one to two times per day.

N-acetylcysteine (NAC) — This has been described as “a precursor to glutathione.”23 It is a powerful antioxidant and is used in IV to treat acetaminophen (Tylenol) overdose. As an inhalant, it helps break up mucus obstructions in the bronchial tree.

Orally, it can help preserve kidney function and has been used to treat psychiatric disorders and substance abuse. He recommends taking 600 mg, two to three times per day.



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