Covid-19 is a very serious virus. It is not to be taken lightly. We have followed it very closely since there was first news coming out of China as the reports already back then were highly concerning. This led us to take profits in our portfolios at a time when markets were near all time highs. There will be a time to get back in again but, given the economic impact is still unknown, we believe there will be no real rush to do so.
The last few weeks in particular have been extraordinary, with global shutdowns around the world, overwhelmed hospital systems, capital market meltdowns and just overall general panic at every level. The biggest sense of frustration is regarding the fact that we are facing an enemy that nobody yet knows how to beat and that we were for the most part, unprepared for. As in the investment world we are in the business of reading research on everything and anything, we of course could not help ourselves and started also to read all the research we could get our hands on around this virus. The objective was to simply see if there was anything that could be done to mitigate the damaging effect of this virus, if one were unfortunate enough to get it.
Therefore, over the last week we have been looking into all the material available on COVID-19 and we have come across some pretty compelling research we would like to share with you.
There are reports coming out of China, where the virus was first found, that the disease severity varied remarkably across the spectrum from mild disease with almost no symptoms in some, to very severe and potentially fatal outcomes for others (link to article #1 below). The disease appeared to be mild in the first week, before you either recovered, or faced a steep decline into viral pneumonia (link #2) that could ultimately lead to death, primarily for the elderly or those with underlying conditions.
The only thing that could have accounted for these differences in reaction to this virus were the innate immune responses of the individuals themselves. The disease appeared to affect the elderly to a greater extent than the young, with almost no evidence of the disease in infected children. Those with either hypertension or diabetes, fared the worst, with a very high percentage of incidents ending in death.
We initially focused on the first line of defense in the body against this virus which is the action of the cilia in the lung’s epithelial cells (link #3). We found studies that showed that the CBF (Cilia Beat Frequency) declined with age, almost linearly (link #4), and also declined with colder temperatures (link #23), was negatively impacted by smoking (link #7) and pollution, and that it seemed to be modulated by the concentration of nitric oxide (NO) in the epithelial cells themselves (link #8).
Looking further into the nitric oxide question, studies emerged that indicated that people with cardio vascular disease and hypertension (link #9) and diabetes (link #10) all had impaired abilities to synthesize nitric oxide in their cells. The implication was that their CBF would be dangerously low.
We then did more research and discovered that nitric oxide synthesis ability declined linearly with age (link #5) , with the average person losing a large percentage of their nitric oxide synthesis ability by the age of fifty.
Pregnant woman were also being spared the worst of the disease. It appeared that during pregnancy, a protein called “relaxin” was being produced which resulted in CBF being increased in pregnant women (link #6). Research studies also indicate that during lung infections our lung cells were upregulating nitric oxide production in the lungs epithelial cells themselves .
The obvious conclusion is that the ability to produce nitric oxide in cells had to be the result of an immune response. It was clear that those with a compromised ability to upregulate NO themselves i.e. the hypertensives ( prevalent among the black population in the U.S. - see link #40 and #42) , the diabetics, and the asthmatics, who are apparently unable to rally their innate nitric oxide synthesis, would not be getting the much needed antiviral and immune response benefits of nitric oxide synthesis . Men were also disproportionately affected by the virus being sixty-five percent more likely to die from COVID-19 than women (see link #39). Women it appears were being protected by their estrogen which stimulates Nitric Oxide synthesis (see link # 41).
A turning point came when we found three studies , one for Porcine Respiratory Coronavirus (link #12 , a coronavirus for pigs), one study for SARS (link #13) and one for the common cold (link #20), that showed that nitric oxide itself was impairing the ability of these viruses to replicate in epithelial lung cells, and actually was shutting down the ability of the virus to copy it’s RNA (link #11). The results of the tests were compelling.
This led us to discover additional research that confirmed that the nitric oxide was acting directly on the viruses in the lung cells (link #11), and the cells themselves were trying to make as much of it as they could. The other interesting fact was that the virus called SARCoV2 which causes covid-19 is considered to be a strain of SARCoV (link #22) on which the study was based in which NO significantly depleted the virus in vitro. What if both viruses shared the same RNA replication strategies, in which case then NO might work for SARSCoV2 (the virus that’s causes the disease called COVID-19) as well?
In addition to all this, there have been many media reports that taking ibuprofen or naproxen makes the disease worse (link #16). There is research that pointed to a link between NSAIDS (ibuprofen and naproxen) to a reduced ability of your body to synthesize nitric oxide (link #17). Furthermore those patients critically ill with MERS ( a similar coronavirus) receiving steroids were more likely to require mechanical ventilation (see link #26) and the reason again links to the ability of steroids to inhibit Nitric Oxide production ( see link #27).
Recent reports are showing that COVID-19 causes widespread blood clots in the lungs creating tiny blockages that prevent blood flow and access to oxygen (see link #43). Research indicates that nitrates might play a critical role in regulating platelet reactivity and overall blood clotting upon it’s reduction to Nitric Oxide in blood vessels especially under hypoxic conditions as would exit under a COVID-19 infection (see link #44). It appears that as SARCov2 attaches to cells using the ACE2 Receptor it pulls the receptor into the cell reducing ACE2 expression (see link #46). Since ACE2 expression modulates eNOS expression, decreases in ACE2 expression can cause a drastic decrease in Nitric Oxide concentrations leading to increased blood pressure, cardiac stress and blood clotting (see link #45).
We also discovered a trial just announced a few days ago at one university that is now testing the use of Nitric Oxide on COVID-19 patients (link #18). Furthermore, the FDA has just approved a device for home use that injects nitric oxide gas into your lungs as a treatment for COVID-19 (link #19). There is also another clinical trial just announced incorporating Nitric Oxide gas as a prophylactic for healthcare workers (see link #36). Chloroquine (the anti-malarial drug) also stimulates nitric oxide synthesis in human endothelial cells (see link #38) however it’s effectiveness might be impaired by the inability of some patients to synthesize NO themselves.
Looking at the infection curve of COVID-19 in Japan versus France (see link #28) we can see that despite almost “no social distancing” going on in Japan (see link #29) Japan has had very few cases of COVID-19 with a relatively flat curve trajectory and yet the bullet trains there are packed every day. When we compare the amount of dietary nitrate (precursor to NO production by the gut microbiome) consumed in Japan versus France, we found the Japanese traditional diet has the world’s highest quantity of nitrates at 18.8.mg/kg/bw/day (five times the acceptable daily limit of 3.7 mg/kg/bw/day). France’s daily consumption of nitrates by contrast was 40% of the acceptable daily limit of 3.7 mg/kg/bw/day. The difference in the infection rate in both countries is dramatic (see link #28).
The mortality rate of COVID-19 also varies dramatically by country with Spain at 7.5% and Italy over 10% at the higher end and Germany at 0.5% on the low end. Although demographic factors, healthcare efficiencies, social distancing may account for a large share of the differences the fact remains that the gap is very large. Looking at the German diet it is rich in fermented vegetables such as Sauerkraut which contain the bacteria “Lactobacillus Plantarum” . Supplementation with this bacteria increased the bioavailability of Nitric Oxide in vivo (see link #31) rather dramatically. Also of interest was comparing the urinary nitrate excretion levels in 48 populations and 30 countries in the world (see link #35) with the death rate from Covid-19 in total confirmed deaths per million population (see link #34). A very clear correlation is shown with the low nitrate excretion countries USA, Scandinavia, UK, Spain, Italy and Portugal exhibiting the highest high death rates and the high nitrate excretion countries Japan, China, South Korea all exhibiting the lowest death rates.
It appears that, using the mosaic theory, all roads were leading to nitric oxide (NO) as the key to this entire problem. The only question then remains how can we raise the level of nitric oxide in our lung cells ourselves?
More research on that also produced good news as something as simple cardiovascular exercise (link #25) and beet juice (from beet root powder) reliably boosted the concentration of nitric oxide in our lung cells, enough to raise the concentration of NO in our exhaled breath by large percentages (link #21). It is important however to make sure to take plenty of vitamin C at the same time so as to avoid the formation of nitrosamines (see link #32). There is also evidence that L-citrulline (Links #14 and #15) also does a good job increasing nitric oxide levels as well but may exasperate inflammation in certain situations (see link #33) as it is linked to your immune response. For that reason the healthiest choice remains to stick with the beet root powder and vitamin C . The difference is that with dietary nitrates (Beet root powder) it is bacteria in your gut that produce the nitric oxide. With L-Citrulline your own cells produce it from L-Citrulline’s derivative L-Arginine.
Additional research has revealed additional information as to why nitric oxide is so important in COVID-19 patients (see link #37) . Without nitric oxide our cells suffer from hypoxia (lack of oxygen) and are subjected to oxidative stress. Researchers recent discovery of a furin cleavage site on the spike protein of SARSCov2 lead to an additional insight that the virus must be cleaved by furin enzymes to become bioactive. Without furins there is no viral replication. Please note that hypoxia , oxidative stress and nitric oxide dysregulation are all signs of cardiovascular disease, diabetes , hypertension and cancers . These are the exact health issues affecting the most severe cases of COVID-19 . When cells suffer from oxidative stress they activate HIF-1 , initiating hypoxia signaling . This triggers an increased expression of furins (enzymes) which in turn leads to viral cleavage and replication of the virus. Cells that are well oxygenated will in turn deactivate HIF-1 reversing the process shutting down viral replication. Hypoxia will attempt to stimulate nitric oxide production in cells in order to re-establish the oxygen balance required. As nitric oxide production rises blood vessels and airways become dilated improving oxygenation in the lungs. The ability of cells to do so is strictly dependent on the state of oxidative stress and redox balance in the cells themselves. The problem here is that in the critically ill oxidative stresses are elevated and the ability to generate nitiric oxide can be impaired. Here is where vitamin C, a well known anti-oxidant , becomes crucial to reducing oxidative stress and rebalancing the redox state allowing for more nitric oxide to be produced. This is the reason Chinese doctors were able to successfully treat COVID-19 patients with large doses of vitamin C.
It looks promising at this stage that if we can keep these NO levels high, if we are unfortunate enough to be exposed to this virus (hopefully not), we may be able to be spared the worst it has to offer. In any event it appears nitric oxide has a host of other health benefits (increased stamina and blood flow) whether you ever catch COVID-19 or not, and is considered an anti-aging supplement (link #24) to boot!
This is a global pandemic and it is very serious. We must adhere to the advice of the health professionals and wish them the best and thank them for all the efforts they are going through, and the personal sacrifices and risks that they are taking, to keep us all safe.
We wish everyone the very best during this crisis. It is a time for reflection and to be there to help those that we know, particularly the elderly and the compromised, who may need additional assistance, in order for them to limit their exposure to this virus as much as is humanly possible.
Ultimately, this too will pass. Be safe.
The Summerhill Team
Disclaimer: We are not scientists or medical professionals and the basis of these findings is finding patterns in the conclusions offered through accessible scientific research . All we have done is connect the dots. We would welcome any input from the scientific community in respect of our findings .
Links Referred To Above:
For more on Nitric Oxide, by an authority on the subject, Nathan Bryant, PhD, please see below: