September 1, 2020
We now have the strongest evidence to date that IL-6 plays a direct role in hypoxia in COVID-19, and as it turns out this is bullish for the use of vitamin D and lactoferrin.
Background on IL-6 and COVID-19
I first reported on April 6 that interleukin-6 (IL-6) levels often rise to very high levels in COVID-19 and are an extremely strong predictor of whether someone will require ventilation. On April 22, I reported on one study showing small blood clots in the blood vessels of the lungs and another finding that people who were treated with tocilizumab, an IL-6 blocker, had a 75% lower risk of dying and a 58% lower risk of requiring ventilation. I suggested from these studies that IL-6 contributes to clotting in the small blood vessels of the lungs, and that this drives hypoxia.
I reported on another study on June 5 that found those who were treated with tocilizumab were 60% less likely to be admitted to the ICU, and 0% of them required ventilation, compared to 13.8% of those who were not treated with the drug. Five days later, I reported on three studies suggesting that those treated with the drug have 60-80% lower risks of ICU admission or mortality, but only if they had very high CRP levels (indicating intense, acute inflammation) and were treated early in the course of their disease.
Other studies accumulated with similar results, and I haven't covered them all in the newsletter, because they kept showing the same old thing and I've been waiting for more conclusive studies to come out.
Specifically, up until this weekend, every paper on tocilizumab has been observational. This means that the decision to use the drug was made at the discretion of the physician, or because the protocol was changed at some date, and researchers later looked at how those patients fared. Since the drug wasn't allocated randomly to similar patients treated under standardized conditions, studies of this nature are poor evidence of cause-and-effect relationships. The best design for determining causality is a large, randomized controlled trial (RCT).
The First RCT of Tocilizumab, an IL-6 Blocker
The first RCT testing tocilizumab was just released on Saturday as a preprint* and is destined for publication in The Lancet.
It was conducted over one month, between February 13 and March 13, in six hospitals of two provinces in China. During that time, the case loads decreased and the survival rates increased, which resulted in fewer people than they'd hoped for the trial, and in a population that had lower inflammatory scores and better survival rates than would have been ideal to show a strong effect of the drug.
They designed the protocol expecting to triple the cure rate from 10% to 30% among patients with COVID-19 pneumonia. For this, they expected to need 85 patients in each group. Instead, they recruited only 65 patients total, and the cure rate was 87% in the control group and 94% in the tocilizumab group. The effect of the drug was not statistically significant, meaning it couldn't be distinguished from the effect of chance. That is not surprising, given that the baseline cure rates were nine times better than they had expected when designing the trial, giving little opportunity for the drug to improve them.
CRP levels were only 20 mg/L, and one previous observational study had suggested the drug mainly impacts mortality in people with CRP over 150 mg/L.
Nevertheless, the drug lowered IL-6 levels as expected and had a strong impact on hypoxia, defined as oxygen saturation below 93%. 67% of those in the control group had their oxygen saturation get worse, but only 8% in the treatment group, representing and 8-fold reduction.
Evaluated over the course of two weeks, the rate of recovery from hypoxia began diverging between the groups on day 8, and the difference became statistically significant on day 12. The recovery rate plateaued at about 60% in the control group, but increased to about 80% in the tocilizumab group by day 14.
Adverse events were 4.5 times more common in the treatment group (59% vs 13%), but they were mainly limited to changes in liver enzymes, white blood cells, and neutrophils. These were temporary and there were no serious adverse events.
The drug had no impact on viral loads or the time required to clear the virus.
This study was small, underpowered, and it was neither double-blind nor placebo-controlled. However, it is the first RCT of the IL-6-blocker tocilizumab, and as such it represents the first direct evidence that IL-6 is a major cause of hypoxia in COVID-19. I still suspect it at least partly mediates its effects by stimulating clotting in the blood vessels of the lungs.
Vitamin D, Lactoferrin, and Echinacea
This strengthens using the effects of foods or supplements on IL-6 as a screening tool for suggesting their potential positive or negative impact on COVID-19 outcomes.
In particular, it strengthens the likelihood that the vitamin D/COVID-19 connection is a causal one, and supports the potential of lactoferrin to provide a benefit.
In March, I had originally taken the position that any unnecessary vitamin D supplementation should be avoided on the basis that it could increase ACE2, the entryway for SARS-CoV-2, the coronavirus that causes COVID-19, to enter our cells. On April 28, I released Version 3 of The Food and Supplement Guide of the Coronavirus where I revised this stance to suggest keeping vitamin D status close to 30 ng/mL 25(OH)D, on the basis of the first observational study connecting vitamin D status to better COVID-19 outcomes. I had reviewed that study a few days earlier in this newsletter, where I suggested that normal vitamin D status may primarily act to prevent severe and fatal COVID-19 outcomes by restraining IL-6 from reaching extremely high levels during acute inflammation. Here is the brief review of the literature on vitamin D and IL-6 I provided at that time:
Vitamin D and IL-6
A meta-analysis of four trials in middle-age and older-adults found no effect of vitamin D on IL-6. Another meta-analysis reported four studies that all found no effect of vitamin D on IL-6 in hemodialysis patients. Another pooled the results of eight studies and reported no effect in obese and overweight subjects. In diabetes, three out of five studies found that IL-6 was lower in vitamin D supplementation groups than in controls, but statistical significance was only achieved in one study, and when the results of the five studies were pooled together, they were not statistically significant.
However, in heart failure, vitamin D supplementation reduced IL-6 in one trial but not another. In diabetic kidney disease, vitamin D supplementation reduced IL-6 in all three trials.
Intramuscular injection of 300,000 IU vitamin D reduced IL-6 in patients with ventilator-associated pneumonia. Since COVID-19 causes pneumonia, this is arguably the context that is most relevant to COVID-19.
The Most Likely Explanation
It seems as though vitamin D has very little impact on IL-6 in studies of chronic illness where the inflammation is typically moderate, while it sometimes has a dramatic effect on IL-6 in severe or acute inflammatory conditions.
Since IL-6 can rise 10- or 20-fold higher than normal levels in COVID-19, it seems quite likely that vitamin D could help keep it closer to normal levels. Since IL-6 could be playing a direct role in hypoxemia and respiratory failure, that makes a strong case for testing whether vitamin D could prevent the disease from progressing in severity.
While vitamin D has many effects on the immune system, including the production of antiviral peptides, the evidence suggests a rather weak but meaningful impact on infection risk and a much more powerful effect on severity and mortality. Therefore, I don't think that restraining IL-6 is the only relevant impact of vitamin D, but I believe it may just be the most important one.
As the observational evidence on tocilizumab began to accumulate, I suggested that bovine lactoferrin, which has been shown to lower IL-6 in pregnant women with various inflammatory conditions, may be useful. I first suggested this on June 5, then suggested it could help normalize iron metabolism in COVID-19 a day later, and then did a deep dive into the antiviral properties and IL-6-lowering properties of lactoferrin on June 8. Most recently, I expanded on the antiviral properties of milk and whey protein, where I suggested that 20-40 grams per day of a high-quality whey protein would be the best way to obtain sufficient lactoferrin in its natural state to lower IL-6 while also taking advantage of the other antiviral properties of the proteins.
In Version 1 of The Food and Supplement Guide for the Coronavirus, released on March 17, I suggested echinacea could serve as a “potential add-on,” which, in version 2, became a “potential add-on” for “if and when you get sick.” This was based on studies in the first SARS virus suggesting that interferon was harmful while nitric oxide was helpful, and the fact that echinacea appears in cell studies to exert antiviral properties more through stimulating nitric oxide than interferon. However, Version 5 of the guide, released on August 17, removed echinacea on the basis that it can increase IL-6. While animal models of COVID-19 seemed to confirm the potential harmfulness of interferon, the human evidence that IL-6 was such a big player just kept growing and growing. I'm not convinced that echinacea is harmful in COVID-19, but I feel much more uncertain about it than I did in March.
The Bottom Line
This new RCT confirming the causal role of IL-6 in hypoxia strengthens the suggestion that vitamin D may restrain COVID-19 from reaching a severe or fatal outcome by restraining large acute elevations of IL-6, and strengthens the possibility that lactoferrin could be useful. Keeping 25(OH)D at 30-40 ng/mL and using 20-40 grams of whey protein per day are likely to be the best ways of taking advantage of this.
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Stay safe and healthy,
Chris
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I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.
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*Footnotes
* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.