Could Elderberry Cause a Cytokine Storm in COVID-19? Extremely Unlikely.

Disclaimer: Nothing in this post constitutes medical advice. Please see the disclaimer at the bottom of the post for more details.

When I first came out with The Food and Supplement Guide for the Coronavirus (newly revised and released as Version 5.0 this week), many people questioned my recommendation to use elderberry extract as first-line defense against the coronavirus (after the critical hygiene and social distancing recommendations made by all the public health experts). They worried that elderberry could contribute to the “cytokine storm” seen in COVID-19, a condition where the immune system responds strongly and dysfunctionally to the virus, causing damage to multiple organs and potentially causing death.

In this post, I explain why I consider it extremely unlikely that elderberry poses this risk.

First, let's look at the claim.

The Claim: Elderberry Could Cause or Worsen a Cytokine Storm

The most respected source claiming this is a COVID-19 FAQ on the site of the Andrew Weil Center for integrative medicine, which states this about elderberry:

Q: Why is elderberry considered safe for prevention but recommended to stop with symptoms or positive COVID-19 test results?

A: Elderberry extracts may help to prevent the early stage of corona virus infections, which includes COVID-19. Elderberry contains compounds which decrease the ability of viruses to infect cells. Elderberry is considered generally safe and in influenza B (cause of common cold), use of elderberry shortens the duration of symptoms. However, as a part of its immune supportive actions, elderberry increases immune cell release of tiny chemicals called cytokines. Specifically, elderberry increases the release of a cytokine called IL-1B which is a part of the inflammatory reaction to COVID-19 that can result in acute respiratory distress. For this reason, to minimize the possibility that elderberry could aggravate the inflammatory “cytokine storm” associated with the more severe COVID-19 infections, it is recommended to stop elderberry at the first signs of infection (fever, cough, sore throat) and/or if you test positive for the virus.

Examine.Com takes a more moderate stance:

Elderberry has some evidence for the treatment of influenza[67] and the common cold,[67][68] but very few studies exist thus far. Some people on the web have warned that it could initiate or exacerbate “cytokine storm”, based on a study circulating around that shows increased cytokine production from elderberry intake.[69] The authors propose that “in addition to its antiviral properties, Sambucol Elderberry Extract and its formulations activate the healthy immune system by increasing inflammatory cytokine production” (as cytokines are a natural and critical part of immune responses to pathogens). Cytokine storm though isn't a mere bump in cytokine production, it's a severe overreaction to a pathogen by the immune system, with a massive increase in immune cells and the cytokine messengers they release. In cases of severe flu, it's associated with outcomes ranging from lung inflammation to death.[70] Although it appears unlikely that a low-to-moderate dose of elderberry for prevention would initiate cytokine storm, nobody knows if taking it (especially in large amounts) when symptoms are severe may have adverse effects. Discuss supplementation thoroughly with your physician before using it, as evidence is constantly changing for COVID-19.

The first place I heard this claim was on SurvivalBlog, which I think might be the origin of the claim. This blog is run by a former US Army Intelligence officer and technical writer who describes himself as a “survivalist author” and a “Constitutionalist Christian libertarian.” The post about elderberry cites a single study  showing that when immune system cells known as “monocytes” are incubated with elderberry extract, they increase their production of cytokines. The author notes that cytokine storms occur in COVID-19, so elderberry might make them worse, and concludes as follows:

Moral of the story: Elderberry syrup, a prime tool in the arsenal against seasonal flu, might not be helpful against this Wuhan coronavirus. Might even make it worse. It’s probably too soon to tell, so keep a watch out for news about a connection.>

This post seems to have dispersed the claim via Reddit through much of the Internet.

Before examining this claim, let's take a look at the nature of the “cytokine storm” being observed in COVID-19.

What Is a Cytokine Storm?

Cytokines are small molecules that communicate the need for different parts of the immune system to step up to action. They include chemokines, which cause cells of the immune system to move into a certain location; interferons, which are central to the antiviral defense and are named after their ability to “interfere” with viral replication; lymphokines, which are made by immune system cells known as lymphocytes; and tumor necrosis factors, named after their ability to kill tumor cells.

A “cytokine storm” is a strong, dysfunctional immune response that contributes to organ damage and death. It is not simply an “overreaction” of the immune system. It is not characterized simply by “too much” of an immune response. In order to understand what is happening, we need to look more specifically at which parts of the immune system are overreacting, and which are underreacting. 

The Nature of the Cytokine Storm in COVID-19

The possibility that a “cytokine storm” contributes to the severe disease state and death of COVID-19 originally came from a report in The Lancet that was published on February 15 (1–3).

At the time, the blood levels of various cytokines and other markers of inflammation were all pulled from patients’ medical records after they had been discharged from the hospital, or, in many cases, died. Since the data was not collected in a systematic manner to look for the nature of the cytokine storm taking place, it is less valuable for understanding what is happening than newer data that was collected for that purpose.

The pattern that is emerging from the newer data is that severe COVID-19 cases, when compared to milder cases, are marked by the following:

• Increased neutrophils. (4) Neutrophils are white blood cells that have the potential to cause tissue damage by generating bleach, hydrogen peroxide, and other toxic substances while trying to kill microbes. 

• Lower levels of lymphocytes, especially CD4 and CD8 T cells and natural killer cells. (4–8) Lymphocytes are white blood cells that are found most abundantly in the lymphatic system, which allows a fluid called lymph to bathe our tissues and return fluids to the bloodstream. CD4 T cells are “helper T cells” that help activate CD8 “killer T cells,” which kill cells that are cancerous or infected with viruses. While T cells respond to signs of specific infections called “antigens,” natural killer cells are generalists, and will kill any cell that appears to be infected with a virus while the T cells are preparing to mount a more specialized response. 

• Higher levels of interleukin-6 (IL6, or IL-6). (4–10) IL6 is a chemical messenger with a wide variety of inflammatory and anti-inflammatory functions. It increases energy consumption and heat generation, plays a role in fever, and stimulates the production of neutrophils, which are the one class of white blood cells that are elevated in severe cases of COVID-19.

There are a variety of other markers of inflammation that have support from fewer studies, or conflicting results between studies (1,4,6–8). These include tumor necrosis factor-alpha (TNFα), interferon-gamma (IFNγ), and a wide variety of other less often measured cytokines. Other inflammatory factors that are elevated in severe cases are more the result of the cytokines released than the cause. These include C-reactive protein (CRP), which is released by the liver to clean up dead and dying cells; D-dimer, released as blood clots are broken down; and ferritin, a protein that helps sequester iron to prevent it from interacting with hydrogen peroxide to aggravate the risk of tissue damage, and to prevent bacteria from using it to fuel their own growth.

Overall, recent studies have identified the neutrophil-to-killer-T-cell ratio as the strongest predictor of disease severity (4), IL-6 as the strongest predictor of requiring ventilation (9), and low lymphocytes as the strongest predictor of death (11).

This obviously is absolutely not a case of an “overactive immune response” at all. It is a dysfunctional immune response, characterized just as much by things that are too low (lymphocytes and natural killer cells) as it is by things that are too high (neutrophils and IL-6).

Where Are the Cytokines Coming From?

In cytokine storms, the cytokines are thought to be made by lymphocytes, or by other cells known as macrophages. Macrophages are named from the Greek meaning “big cells that eat” and they specialize in gobbling up and breaking down anything that doesn’t belong in a healthy body. Macrophages are made from their predecessor, monocytes. While monocytes circulate in the blood, they settle down in inflamed tissue and turn into macrophages there. That means macrophages can be measured in samples of inflamed tissues (for example, if lung tissue were taken from COVID-19 patients, it would probably be very high in macrophages) but not in the blood (12). Lymphocytes are low in severe COVID-19, so the cytokines probably come from macrophages (7).

We can gain some insights from looking at severe acute respiratory syndrome (SARS), which was a major outbreak in 2003. The coronavirus that causes COVID-19 is so similar to the one that caused SARS that it is technically called SARS coronavirus-2 or SARS-CoV-2 (13).

In particular, animal studies provide much more insight about how things work, because we can take a take more samples from the tissues we are interested in, such as the lung, and because we can genetically manipulate them or manipulate them with chemicals that block certain pathways to better understand what is happening.

In SARS-infected mice (14), the virus suppresses and evades the early interferon response, allowing it to replicate extensively without the immune system mounting an effective response. Large numbers of macrophages and neutrophils infiltrate the lung. The macrophages make type 1 interferon, which increases other cytokines such as TNFα and causes T cells to kill themselves in a process known as “apoptosis.” The cytokines also cause blood vessels to become leaky, which would compromise the delivery of nutrients to the lung tissue and the delivery of oxygen from the lungs to other tissues. Blocking the TNFα with a specific antibody, or genetically engineering the mice to make them unable to respond to type 1 interferon, rescues them from the lung pathology and allows them to survive even after being infected with an otherwise lethal dose of the virus. 

Although the neutrophils may be damaging to the lung tissue, the macrophages seem to be the primary culprit. Blocking the TNFα or the interferon response rescues the mice from lung damage and death without affecting the neutrophil content of the lung. By contrast, these treatments dramatically lower the macrophage content. 

From SARS-infected mice, it seems the process goes something like this:

• The virus suppresses and evades the initial interferon response, allowing it to replicate and reach large numbers.

• The high viral load elicits a high macrophage content in the lung.

• The macrophages cause a late but large interferon response, which elicits more macrophages in a vicious cycle, leads to the death of T cells, and initiates a cytokine storm that causes blood vessels to leak and causes damage to the lung tissue.

SARS isn’t the exact same disease as COVID-19, even though they are similar, and not everything in mice will translate directly to humans. However, we should keep in mind three things: 1) in COVID-19, what happens in the lung is probably driving most of what is found in the blood; 2) the key culprit cells in the lungs are probably macrophages; and 3) the exact cytokine profile in the lung might be different from the one found in the blood.

With that said, we can draw some connections between the SARS-infected mice and what we find in humans:

• TNFα plays a major role in SARS-infected mice, and two studies have shown higher TNFα levels in the blood of severe COVID-19 patients (1,8).

• The cytokine storm elicited by macrophages in the lungs of SARS-infected mice lead to the death of T cells, and, as reviewed above, T cells are consistently low in severe COVID-19 patients.

• Neutrophils are elevated in the lungs of SARS-infected mice and in the blood of severe COVID-19 patients.

So, when looking at whether elderberry is likely to aggravate the cytokine storm, we should be considering the primary features found in the blood of severe COVID-19 patients (lower helper and killer T cells, lower natural killer cells, higher IL-6, higher neutrophils, and higher TNFα) as well as the probability that infiltration of the lung with macrophages is the key issue driving everything and the possibility that interferon is a major cytokine player within the lung.

Does Elderberry Increase Inflammatory Cytokines?

Well, let’s cut to the chase.

The one and only randomized, placebo-controlled trial that tested this in humans fed people 1000 milligrams of elderberry extract per day for 12 weeks and found no difference in inflammatory markers whatsoever (15).

That’s the most important piece of evidence, and that study suggests the answer is no, elderberry doesn’t increase inflammatory cytokines in humans.

However, the true answer is probably more complex than this, so let’s take a look at the other studies, done in isolated cells and in animal experiments.

Comparing a Cell Study to a Randomized, Placebo-Controlled Trial

The one study cited in support of this by the SurvivalBlog and by Examine.Com looked at this question by taking monocytes from the blood of healthy volunteers and then incubating them in elderberry extract (16). Elderberry stimulated the production of TNFα and IL-6, both of which are of concern for the COVID-19 cytokine storm.

However, the one randomized, placebo-controlled human trial that was done found no effect at all of elderberry on TNFα or IL-6. In fact IL-6 was nearly identical across groups and from baseline to end, while TNFα, though not statistically significant, was 20% lower at the end of the trial in the elderberry group compared to the control group, and 32% lower at the end of the elderberry period compared to the elderberry group at baseline.

These two studies are actually excellent as a direct comparison. The cell study was done on monocytes isolated from the blood of healthy volunteers. The human trial was done in healthy volunteers, who in fact have monocytes circulating in their blood that are perfectly capable of producing both TNFα and IL-6, both of which are measurable in the blood. 

Clearly and obviously, if direct contact between elderberry and a monocyte causes an increase in TNFα and IL-6, but a human eating elderberry extract does not experience a rise in TNFα and may even have it fall, then the relevant components of elderberry that are having this effect on monocytes are not reaching the monocytes within the live humans in the form that would have this effect, or something that is present in the live human but not the isolated cell is eliminating that effect.

Other Cell Studies 

All that said, cell studies are not at all in agreement that elderberry increases inflammatory cytokines:

• In isolated human macrophages, elderberry extract inhibits the production of TNFα and IL-6 that is otherwise caused by seven different stimuli derived from bacteria that cause inflammation of the gums (periodontitis). It also inhibited neutrophil activation. (17)

• In isolated mouse macrophages, elderberry decreased the amount of TNFα and IL-6 generated by lipopolysaccharide (LPS), a component of the cell wall of many pathogenic bacteria (18).

• In gingival fibroblasts, which are collagen-producing cells found in the gums, elderberry slightly reduced the production of IL-6 in response to LPS (19).

• When LPS derived from E. coli was mixed with serum taken from healthy human volunteers, it caused the TNFα to increase in the serum. Elderberry blunted the rise in TNFα by up to 86%, depending on the concentration and the type of extract (20).

By contrast, a study using dendritic cells from mice came to a more nuanced conclusion (21). Dendritic cells are immune cells that present antigens to T cells. When they were exposed to two types of bacteria, L. acidophilus and E. coli, they increased their production of TNFα and IL-6. Elderberry increased the IL-6 and TNFα response to L. acidophilus, but was neutral toward the TNFα response to E coli. Elderberry had a more complicated effect on the IL-6 response to E coli. A low concentration of elderberry spiked the IL-6, but high concentrations had less and less of an effect.

And then finally, just as the first study in human monocytes found increased TNFα and IL-6, so did a second study in human monocytes (22).

Let’s relate this back to what we know about the cytokine storm in COVID-19:

• We are primarily concerned about macrophages inside the lung producing the cytokines, and perhaps neutrophils, not monocytes circulating in the blood. Elderberry is consistently anti-inflammatory in macrophages and inhibits neutrophil activity.

• The cytokine storm of COVID-19 is associated with deficient T cell activity. Activating an inflammatory response to bacteria in dendritic cells, which are responsible for activating T cells, is probably a good thing.

Animal Studies

As we saw in our comparison of monocytes taken from healthy volunteers to actual healthy human volunteers, what happens in a cell study doesn’t always translate to a study done in a living organism. This is because when we eat something, it gets broken up and distributed to many different cells of many different organs, often being digested or metabolized into components that are fundamentally different from what was in the original product. Further, no particular type of cell is found uniformly through the body. In particular, when we are looking at the immune system, it can be far more relevant whether the cell moved into a particular location (for example, macrophages infiltrating the lungs in SARS or COVID-19) than whether it would have been stimulated if it came into contact with something we ate.

While it’s also true that what happens in animals doesn’t always translate to what happens in humans, animal studies still reflect the reality of a living organism in a way that cell studies never can. 

So let’s look at the two animal studies I was able to find:

• Obese mice have higher TNFα and IL-6. Elderberry doesn’t change the IL-6, but it lowers the TNFα (23).

• When elderberry was given to healthy mice, it did nothing to IL-6. However, when the mice were treated with a chemical that causes type one diabetes, IL-6 went through the roof, and elderberry cut it in half (24).

These two animal studies are in agreement with the human study that elderberry does nothing to IL-6 in healthy humans or animals, though it might lower TNFα a little in humans. The animal studies further suggest that in pathological conditions, elderberry either has no effect or reduces each of the two cytokines.

Elderberry Has Never Caused A Cytokine Storm in the Flu

It's worth noting here that cytokine storms can occur in severe cases of the flu (31), yet two randomized controlled trials have been performed in humans with the flu (28), and none have noted cytokine storms caused by the elderberry.

What Is the Ultimate Cause of the COVID-19 Cytokine Storm?

In looking at these studies it is easy to lose sight of the fact that the most important cause of the cytokine storm in COVID-19 is the infection itself.

Obviously not everyone is infected to the same extent, and not everyone who is infected develops the cytokine storm. As research progresses, we will probably learn why some people are more susceptible to the cytokine storm than others, for a given level of infection.

However, it is quite clear that the absolute prerequisite for the cytokine storm is the infection itself. And if we are to learn anything from the SARS-infected mice, the main problem is that the virus initially evades the antiviral response, which allows it to reach much higher levels and recruit macrophages extensively to the lungs.

So, while elderberry is consistently anti-inflammatory in macrophages, that’s nowhere near as important as whether elderberry could prevent macrophages from moving into the lungs, and the most important aspect of that ability would be the antiviral properties it has. Never coming into contact with the virus is obviously the most effective way to avoid the cytokine storm. Short of that, a swift, sustained, antiviral response that is already set in motion before exposure to the virus and continues at least until peak viral loads are reached is likely to be the most important defense against the cytokine storm.

Can elderberry do that?

Why Elderberry Is Likely Antiviral Toward SARS-CoV-2

The virus that causes COVID-19 is SARS-CoV-2. It enters cells by docking to the cell using a protein known as ACE2. This is required for it to enter the cell. Only two other known viruses, SARS-CoV, which causes SARS, and a more moderate virus, human coronavirus NL63 (HCoV-NL63) share the same means of entering cells. Although elderberry has not been tested directly against SARS-CoV-2, it is antiviral toward HCoV-NL63. In fact, it directly interferes with the binding of this virus to the ACE2 protein, which stops it from entering the cell (25). Since NL63 shares this mechanism with SARS-CoV-2, this makes it very likely that elderberry has the same antiviral activity toward SARS-CoV-2.

Elderberry also has antiviral properties toward avian infectious bronchitis virus (IBV), which infects chickens and other birds, and appears to compromise the lipid envelope (26). Although IBV is not known to dock to ACE (2,27) all coronaviruses have lipid envelopes, so this might be an additional antiviral mechanism that generalizes to SARS-CoV-2.

Trials using elderberry for the flu (28) or the common cold (29) used 175 mg extract in a lozenge 4 times per day (x/d), 1 tablespoon syrup 4x/d, or a 300 mg extract in a capsule 3 x/d. These trials found that elderberry cuts the duration of the flu in half and cuts the number of days sick with the common cold in half and reduced the severity of the symptoms in half.

The flu, in particular, is very compelling, because two trials have shown it to be effective in humans, and in the lab it has activity against ten different strains of flu virus (as reviewed in (16)).

The concordance between in vitro (in a lab dish) and human trial evidence for the flu, and its activity toward lipid envelopes and ACE2 binding that we would expect to generalize well to SARS-CoV-2, make elderberry a strong candidate as an antiviral for COVID-19.

Since 1000 milligrams per day of elderberry extract has been used safely for 12 weeks with no effects on inflammation and no evidence of any serious side effects or toxicity (15), elderberry also seems harmless to use for COVID-19 prevention, over and above the absolutely essential hygiene and social distancing.

When and How to Use Elderberry?

If you’re comfortable hedging your bets that elderberry would be antiviral toward SARS-CoV-2 without any randomized controlled trials showing that to be the case (I am, based on the evidence I reviewed above), then I think elderberry should be used prophylactically at 700-1000 milligrams extract per day (containing the bioactives found in about 25 grams of fresh berries). 

If you develop a fever, muscle aches, or dry cough, you may have COVID-19 and should seek medical attention, and should follow any medical advice you receive, including continuing or removing elderberry.

But should you, based on the evidence reviewed here, withdraw the elderberry upon the first sign of symptoms or upon diagnosis?

I don’t think that is wise. If the elderberry is indeed antiviral toward SARS-CoV-2, then the overwhelmingly most important way to avoid a cytokine storm is to maintain very robust antiviral defense right through the peak viral loads. The virus continues to replicate in the upper respiratory tract for five days after symptoms develop, and continues to replicate in the lungs for at least ten days after the first day of symptoms (30). Barring medical advice otherwise, I would continue the elderberry at least through this period.

The Bottom Line

My verdict:

• Elderberry is anti-inflammatory in the cells that matter, macrophages and neutrophils.

• Elderberry only seems pro-inflammatory in cells that don’t matter as much as macrophages and neutrophils (monocytes) or cells we probably want stimulated (dendritic cells).

• Elderberry is neutral or anti-inflammatory in animals when the cytokines that matter (such as TNFα and IL-6) are measured.

• Elderberry is neutral toward IL-6 in healthy humans and possibly slightly anti-inflammatory for TNFα.

• The primary issue with the COVID-19 cytokine storm is unlikely to be a dietary supplement crossing paths with a monocyte or dendritic cell. Rather, it’s the increased macrophage content of the lungs. 

• The most important factor in avoiding it, beyond avoiding the virus itself, is a robust and sustained antiviral defense. 

Elderberry has a good chance at providing the antiviral defense, with at best a very, very weak case it could contribute to a cytokine storm. In fact, the evidence suggests that if the cell studies have any relevance, elderberry would have an anti-inflammatory effect in the macrophages of the lung that could perhaps blunt a cytokine storm.

So, the verdict: not guilty. And quite possibly a hero to be discovered.

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Disclaimer

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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