I’ve been struggling with how to start this next installment on viral illness and then I found the following statement on a website.
“Elderberry also upregulates IL-6, IL-8 and TNF, suggesting an indirect effect on viral immune response in the body. Interestingly, elderberry was shown to have this effect but not its major bioactive compound, cyanidin 3-glucoside.”
To begin with, I don’t consider that anthocyanin to be the major bioactive compound of this plant. I only use elderflower for influenza, and I consider its major bioactive constituent to be pectic polysaccharides, but that’s absolutely not important to this conversation.
Also, none of this is meant to say you should never use elderberry. I am just using it as an example to illustrate some of the questions you should be asking yourself about every herbal adjunct you use. How does it work, when shouldn’t a person use it, and are there safer alternatives?
Basically what I have decided concerning the use of elderberry is that while I can’t prove that any of these things will be a problem, I can’t prove that they won’t be. That should be a deciding factor of any risk-benefit analysis.
Honestly, I am relieved by this statement. I am more likely to use black currants or blackberries which contain the same anthocyanins which have the same effect on viral replication[i] without upregulating the primary proinflammatory cytokines. To explain why I find that preferable I am going to talk about the cytokines that are specifically mentioned in that statement.
What Are Cytokines?
Cytokines are just messenger peptides that mediate the inflammation pathways by carrying messages from cell-to-cell. Some are proinflammatory, some are anti-inflammatory, and some that can go either way depending on the situation.
IL 6 and TNF-alpha are some of the more active proinflammatory cytokines and IL-8 is specific kind of cytokine called a chemokine which are involved in chemotaxis or the recruitment of white blood cells to an area. When I was in school I remembered this for tests by thinking of them as chemical taxis.
The answer to this question is not always. I will start by discussing why I wouldn’t necessarily want to upregulate IL-8 which is a chemokine involved in recruiting white blood cells to an area.
Stanford physician Catherine Blish has studied the hyperinflammatory response to severe influenza in pregnancy extensively attempting to understand why many pregnant women become extremely ill when exposed to influenza. She has stated that abnormally elevated chemokine levels common in pregnancy draw too many white blood cells to the lung. “That’s a bad thing in a lung where you need air space.” Getting the flu during pregnancy, especially pandemic strains such as those that caused the pandemics of 1918, 1957 and 2009, carries a heightened risk for pneumonia and death.”[ii]
What she’s talking about here is a cytokine storm. I have a vested interest in this story because it was this flu that killed my great-grandfather Roberts. The clinical presentation of the storms was first associated with the 1918 flu and included accounts of patients drowning because their lungs filled with fluid and blood [iii] My great-grandfather had the flu, but was then well enough to be up and working and literally dropped dead in the field. So it must have hit him fast.
In 2013 researchers examined the lung tissue of 50 victims of 2009 H1N1 who had died of cytokine storms and found they had “remarkably” elevated levels of IL-1 receptor antagonist protein,IL-6, tumor necrosis factor-alpha, IL-8, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-beta, and interferon-inducing protein-10 [iv] which undoubtedly contributed to the over recruitment of white blood cells. People with autoimmune conditions are more susceptible to this type of immune dysregulation.
These cytokine storms trigger a type of viral induced sepsis which is an acute event involving an amped up immune system response that results in a fatal pneumonia. It is usually associated with H1N1,but coronaviruses have sparked storms, as well. For what it’s worth the 2019-nCoV includes a risk of what some researchers are calling Wuhan Pneumonia which seems to be caused by some sort of cytokine storm.
Now let’s stop and think for a moment about what we have already read. Three of the seven cytokines I listed up above are those the marketing article mentioned elderberry upregulating. Researchers found specifically that areas of the lungs that had high bacterial infection also had high levels of IL-6, IL-8[v], so it doesn’t seem prudent to risk exacerbating that.
SARS-CoV-2 is a virus that is associated with these storms and subjects with severe symptoms are exhibiting elevated IL-6 levels. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
They really don’t know why they happen. Some researchers believe it has to do with age and the elderly are currently most susceptible, but most of the victims mentioned in that 2013 paper, were in their mid 30’s. My great-grandfather was also a younger man with no health complications that we are aware of.
So if we know that an illness associated with these storms is circulating, we want to be cautious. Elderberry doesn’t have a long history of use anyway. Here is an article that speaks to herbs that were used successfully during that outbreak by Eclectic physicians.
Since the risk of cytokine storm is not common, I am going to step back a moment to talk about IL-6 and TNF-A. These are both what they call endogenous pyrogens in that they trigger a fever response as a defence mechanism to pathogens. They also act on nociceptive sensory neurons in the body to initiate the sensation of pain.
So even when working with a viral disease where there is not a known association with cytokine storm, we still want to observe the type of discomfort a person is experiencing and pick our adjuncts accordingly. There is no sense in poking a system that’s already in overdrive.
This B/Washington strain that the flu vaccination botched was a particularly hot and achy strain. Several of my clients who normally take elderberry during a cold, told me they thought their syrup was making it worse and asked if I had other ideas. This makes sense to me giving the fact that it elevates cytokines known for initiating those prodromal signs and symptoms.
So in the the name of making better more nuanced choices, you may want to take into account any health conditions that you don’t want to exacerbate. Honestly I wouldn’t recommend elderberry to a client that had any autoimmune disorder, but I am a safety girl and I have enough tricks up my sleeve to work without it.
After reading the Blish interview and the associated study I am going to start recommending that pregnant women not use it during the flu season because they are also at an increased risk of hyperimmunity.[vi]
So what about taking elderberry prophylactically?
If you just are using elderberries as tonic when there is no viral complication, is that such a big deal?
There are some concerns about doing that. We know that “excessive or persistent cytokine production results in deregulated immune activation and plays a role in both the initiation and the amplification phases of immunopathologies.”[vii] This means it is possible that prolonged upregulation of these primary inflammatory cytokines could contribute to initiating or exacerbating an autoimmune disease. I have worked with clients who believe it triggered a flare for them, although I haven’t seen that with elderberry nearly as often as I have echinacea.
TNF-α, and IL-6 are already elevated in people with rheumatoid arthritis and contribute to chronic inflammation of the synovial tissue, joint dysfunction, and consequent tissue damage in the joints. So persistent upregulation could exacerbate their symptoms of chronic inflammation.
There are no human studies that have shown long-term use is safe. There is one study that I can find where the subjects took it for three weeks, but they were looking at diabetes markers as the end result and did not assess final C-reactive protein levels or any other marker of inflammation. Because I know from experience that autoimmune diseases are really no fun, I don’t feel comfortable recommending it without knowing for sure that I am doing no harm.
What really frustrates me to me is that there are plenty of herbs out there that interfere with viral replication. Research in this area is off the charts, right now. We don’t NEED elderberry. So why is the elderberry craze persisting? Call me cynical, but I think the answer to that has something to do with marketing.
I am not saying that everyone who tries to sell you elderberry knows this stuff. It takes a long time to understand the interaction between herbs and cytokines and I still consider myself a novice. Some people out there have just latched on to the idea that just because something is natural it is safe, and they don’t necessarily have the education and experience to know better.
Edited 02 Feb. 2020
I am editing this post to share my friend Thomas Easley’s feedback that this article “maybe even underemphasizes the potential consequences of IL6 in promoting th17 and suppressing Treg differentiation. If you want to burn an infection out with your immune system use elderberry – but beware the risk of catching everything on fire!” He shared this information about IL6 as a regulator of Treg/Th17 balance.
I wanted to share this article, but I have also had a lot of messages about where to study this sort of information about herbs. If you take my local consultation class I teach the basics you need to be an informed consumer. If you want to learn clinical application, I strongly suggest checking out Thomas’ program. He will put you on the right path.
Edited 28 Feb. 2020: I also wanted to add that I received several messages from Chinese Herbal Medicine practitioners who shared that mulberries are a traditional flu remedy and were used prophylactically during the last SARs outbreak. You can read about that in this article.]
[i] Ehrhardt, Christina, et al. ‘A Plant Extract of Ribes Nigrum Folium Possesses Anti-Influenza Virus Activity In Vitro and In Vivo by Preventing Virus Entry to Host Cells’. PLoS ONE 8, no. 5 (23 May 2013). https://doi.org/10.1371/journal.pone.0063657. and Ikuta, Kazufumi, Koichi Hashimoto, Hisatoshi Kaneko, Shuichi Mori, Kazutaka Ohashi, and Tatsuo Suzutani. ‘Anti-Viral and Anti-Bacterial Activities of an Extract of Blackcurrants ( Ribes Nigrum L. ): Anti-Microbial Activity of Blackcurrants’. Microbiology and Immunology 56, no. 12 (December 2012): 805–9. https://doi.org/10.1111/j.1348-0421.2012.00510.x. [ii] Digitale, Erin. ‘Immune Response Turned up High by Flu during Pregnancy, Stanford/Packard Study Finds’. Stanford Medicine News Center (blog), 22 September 2014. http://med.stanford.edu/news/all-news/2014/09/immune-response-turned-up--not-down--by-flu-during-pregnancy--st.html. [iii] Kobasa D, Jones SM, Shinya K, et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature. 2007;445(7125):319–323. doi:10.1038/nature05495. [iv] Gao R, Bhatnagar J, Blau DM, et al. Cytokine and Chemokine Profiles in Lung Tissues from Fatal Cases of 2009 Pandemic Influenza A (H1N1). The American Journal of Pathology. 2013;183(4):1258–1268. doi:10.1016/j.ajpath.2013.06.023. [v] Ibid. [vi] Kay AW, Fukuyama J, Aziz N, et al. Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy. Proceedings of the National Academy of Sciences. 2014;111(40):14506–14511. doi:10.1073/pnas.1416569111. [vii] Salvi V, Gianello V, Tiberio L, Sozzani S, Bosisio D. Cytokine Targeting by miRNAs in Autoimmune Diseases. Frontiers in Immunology. 2019;10. doi:10.3389/fimmu.2019.00015.