Arginine and COVID

Disclaimer: I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and this information is educational in nature.

An Italian clinical trial peer-reviewed and published this past month in EClinical Medicine, one of the journals published by The Lancet, is nothing short of incredible.

It provides rigorous evidence that 3.2 grams per day of the amino acid L-arginine dramatically hastens the improvement in respiratory function in patients that already have confirmed pneumonia and are already suffering from hypoxemic respiratory distress. It may turn out to be lifesaving.

One of the things that is so remarkable about this study is that usually nutritional treatments have to be started early in the course of illness to work. For example, as I covered in my comprehensive review of the vitamin D literature, maintaining high vitamin D status is the single best thing you can do for prevention, and if administered early in the course of illness it is extremely powerful in preventing the illness from getting bad enough to put someone in the ICU. By contrast, if vitamin D is given to people who already have severe respiratory distress — at least in the standard form of vitamin D you would buy in the store — it does nothing at all.

In this case, however, the L-arginine works when things have already gotten very bad.

Background

The protein in the food we eat — especially rich in meats, fish, shellfish, dairy products, and legumes such as lentils, peas, and beans — is made of building blocks called amino acids. One of those building blocks is L-arginine, or just “arginine.”

Arginine is the raw material from which we make nitric oxide.

Nitric oxide plays three critical roles that are likely to be extremely important for COVID protection:

• Since nitric oxide is antimicrobial, the immune system always makes massive amounts of nitric oxide to kill pathogens.

• Nitric oxide is the main vasodilator. This means it dilates your blood vessels, making them wider, and allowing blood to flow more freely. This would protect against clotting.

• In the lungs, nitric oxide combines with another molecule we make from the protein we eat, glutathione, to make nitrosoglutathione. Nitrosoglutathione is our own natural bronchodilator. This means it opens up the airways, just like nitric oxide opens up the blood vessels. This allows us to breathe more freely.

In addition, arginine itself is needed for lymphocytes to proliferate. Lymphocytes are a type of white blood cell, and a key player in our immune system. If your doctor orders a complete blood count (CBC), a panel of tests that is also used to diagnose anemia, it will have the number of lymphocytes found in your blood on it. If lymphocytes can't reproduce, or “proliferate,” their numbers will be low. Low lymphocyte counts are a major predictor of whether a COVID patient will die.

Adults and children hospitalized with COVID-19 have low blood levels of arginine. Arginine levels are even lower in those with severe cases than in those hospitalized for more moderate cases. This appears to be at least partly driven by a type of cell that suppresses the immune response, commonly found in obesity and cancer. These immunosuppressive cells make an enzyme known as arginase that destroys arginine. This depletes the arginine available for lymphocyte proliferation, causing low lymphocytes. The low lymphocytes become the major predictor of death.

Lymphocytes taken from severe patients have trouble reproducing. Dumping a little arginine on top of them helps them start multiplying again.

The short of it is this: patients hospitalized with COVID have increased levels of immunosuppressive cells that make the enzyme arginase. This depletes arginine. Arginine depletion causes low lymphocytes and low nitric oxide. Low lymphocytes are known to drive the risk of death, and low nitric oxide probably plays a role as well by making blood vessels and airways more constricted. This makes blood vessels more vulnerable to clotting risk and airways less able to oxygenate the blood.

The Italian Trial

The Italian trial was double-blind, randomized, and placebo-controlled. This means that neither the medical researchers nor the patients had any idea whether they were getting arginine or a placebo that looked, tasted, smelled, and felt just like it. This is the gold standard.

The placebo and arginine were provided by the manufacturer of the arginine supplement, but there does not appear to be any other external funding. The manufacturer played no role in the design, implementation, or analysis of the study. The trial was conducted in a hospital in Naples, and the authors were affiliated with either the COVID-19 division of a nearby hospital, medical colleges in the area, or Albert Einstein College of Medicine in New York. None of the authors reported any conflicts of interest.

In order to be included, patients had to have all of the following: pneumonia confirmed by chest imaging, low blood levels of oxygen, and low lymphocytes.

They excluded anyone who had a known intolerance to arginine, who was pregnant or breastfeeding, who had various blood disorders, who was on certain immunosuppressive drugs or types of chemotherapy, or who had been having COVID symptoms for more than 15 days.

These patients were, on average, eight days into their illness, but some were as far as two weeks into their illness, and they all had severe cases with serious risk of death.

The patients were randomly allocated to the arginine or placebo group. Both patients received a vial twice a day of a liquid that was sweetened with sucrose and soured with citric acid. These were minor components that served to fully disguise the taste of the arginine. The liquid was the same in the two groups except the arginine group had 1.6 grams of arginine added to each vial.

The treatment being tested, then, was 1.6 grams of L-arginine taken twice a day to yield 3.2 grams per day.

The patients took the arginine or placebo until they were discharged from the hospital or died.

The trial is ongoing and will eventually recruit 290 patients. The findings were so remarkable that they published their interim findings in the September issue of The Lancet's EClinicalMedicine after having put the first 101 subjects through the trial. The arginine group had 48 people while the placebo group had 53 people, although some people died before they were treated, and 45 people received treatment in each group.

It is important to note that the small number of patients involved in the interim results actually makes the results more compelling. While we always want research confirmed with bigger and bigger studies done in different populations to make us confident the effect generalizes across populations, the reason they are recruiting 290 people is because they planned on observing a more moderate effect that would require a larger sample size to generate rigorous statistics. Instead, the results were so big and so consistent that they obtained rigorous statistical evidence with only a third of the people they intended to recruit.

Arginine Hastens Respiratory Improvement

The main endpoint was an improvement in the degree of respiratory support needed. This could be moving from more invasive oxygen support to less invasive forms, or it could mean going off oxygen support entirely. When adjusting for demographics and comorbidities, arginine led to 6.6 times greater odds of improving respiratory support by day 10.

This was statistically significant at a P value of 0.01. That means that, if there were no real effect of arginine, we would only have a 1% chance of observing an effect this big.

By day 20, the placebo group started to catch up. That means that the effect of the arginine was to hasten the improvement in respiratory function, making it far more likely to occur by day 10 rather than by day 20.

Did Arginine Abolish the Risk of Death?

While 6.7% of people in the placebo group died, no one in the arginine group died.

With a larger study, we will probably find that the arginine group experiences some death. For example, if the death rate were brought down to 0.5%, we would need 200 people per group to reliably see one person die. Still, that would represent a 93% reduction in the relative risk of death.

However, the difference does not achieve statistical significance. 3 people in the placebo group died, and none in the arginine group. This has a P value of 0.19 or 0.24, depending on the statistical test used, which means that if arginine does not reduce the risk of death, there would be a 19-24 percent chance of observing a difference this large or larger.

In the context of the interim results of this trial, the arginine appeared to abolish the risk of death, but we will need to see the final publication after all 290 patients have been recruited to get more rigorous statistics.

Either way, arginine is extremely powerful at hastening the recovery of respiratory function and appears so far to be lifesaving.

What Was the Mechanism?

Interestingly, this study did not show any improvement in lymphocyte levels.

That makes me think the improvement in nitric oxide function was the primary mechanism involved, but they didn't test that directly.

Implementing These Findings

In the most recent edition of The Food and Supplement Guide for the Coronavirus, my protocol calls for starting 1.6 grams of L-arginine twice per day on an empty stomach with a full glass of water or prior to a meal, beginning with a positive COVID-19 test or upon experiencing any signs of respiratory distress.

This is not medical advice and this is not a substitute for seeking medical care. Importantly, the patients in the trial were hospitalized, and everyone was receiving the standard of care in addition to either the arginine or placebo.

My rationale is that respiratory distress signals the demand for arginine seen in the patients who were studied, while a positive COVID-19 test combined with any other COVID-19 symptoms increases the probability of having respiratory distress in the future. Since L-arginine is quite harmless in most contexts, and since early treatment is probably always better, it is best to start whenever there are decent signs it might become important, rather than waiting till things get bad.

Often people aiming to increase their arginine levels will use a different amino acid known as L-citrulline. While citrulline is usually easily converted to arginine, the disruptions that occur to amino acid metabolism in COVID are not completely and clearly defined. I would worry that the conversion of citrulline to arginine could be hurt, which would make that strategy less effective. I, therefore, think L-arginine should be used.

Some people with herpes infections experience flareups when supplementing with arginine. While anyone would obviously prefer to have a cold sore than die, if you know you get herpes flareups in response to L-arginine, you may wish to be more conservative about when you decide to initiate its use.

There are also some claims that a different amino acid, lysine, protects against COVID. However, these claims are based entirely off of reporting improvement in people who took lysine without comparing them to anyone else. The authors believed the lysine was antagonizing arginine, and this Italian trial clearly refutes that using the gold standard: the double-blind, randomized, placebo-controlled, clinical trial.

Arginine, the Unsung Hero

These results show, using the gold standard of evidence, that 1.6 grams of L-arginine taken twice a day to yield a total of 3.2 grams per day, may have abolished the risk of death in a group of 48 people with severe COVID-19, confirmed pneumonia, and respiratory distress who were hospitalized and receiving the standard of care. More clearly, it led to an almost 7-fold increase in achieving an improvement of respiratory function within ten days. I believe is likely from improving nitric oxide function, opening up the airways and blood vessels and diminishing the harmful effects of blood clots. While we need the final results from this trial to get rigorous statistics on death, so far we know that arginine is a powerful tool to recovery respiratory function and appears to be lifesaving.

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