Does Elderberry Cause “Cytokine Storms” in COVID Patients?

Elderberry is a staple in many natural medicine toolkits, especially during cold and flu season. Many people are now turning to it as a preventive or therapeutic treatment for COVID-19. It may have some merit in this context, but recent reports that the beloved botanical can set off a storm of hyperinflammation have called its immune-boosting power into question. Elderberry juice

Elderberry Sales Surge

Elderberry (genus Sambucus) supplements were already rising in popularity before the COVID-19 outbreak. A growing number of Americans use extracts, juices, and syrups prepared from the flowers, leaves, and berries of European elder (Sambucus nigra) as their go-to natural remedies for flu and cold prevention.

In 2018, elderberry products ranked fourth among top-selling herbal supplements in the US, reflecting a massive 138.4% increase in sales over the previous year. The long-used medicinal plant continued its upward climb in 2019, with total elderberry supplement sales reaching $113 million nationally.

Then, the coronavirus struck. Immune supplements of all kinds, including elderberry formulas, started flying off retail shelves at a faster-than-usual pace. Immunity product sales also soared online; elderberry accounted for one in every five items sold from Amazon.com’s vitamin and supplements category in April 2020. One leading elderberry supplement brand issued a notice to customers advising of significant order processing and shipping delays following the sudden surge in demand for its products.

The enthusiasm about elderberry in the context of viral infections is reasonable.

One research team demonstrated, flavonoids from elderberry extract bind to Influenza A (H1N1) virions in vitro and, “when bound, block the ability of the viruses to infect host cells.” The plant compounds’ ability to inhibit H1N1  “compare[d] favorably to the known anti-influenza activities” of oseltamivir (Tamiflu) and amantadine, two medications widely used for flu prevention and treatment (Roschek, B et al. Phytochem. 2009; 70(10): 1255-61).

Elderberries are also high in Vitamin C, an essential nutrient with antiviral properties. Some health professionals are today experimenting with high-dose vitamin C as part of a treatment protocol for patients with COVID-19.

But as many embraced the ancient herbal ally, chatter about a possible risk to using elderberry to treat the coronavirus began making waves on the internet.

Claims that elderberry causes Cytokine Release Syndrome, or CRS––also referred to as “cytokine storm” syndrome––painted the medicinal plant as more foe than friend in the battle against COVID-19.

Avoiding the Cytokine Storm

Concerns about adverse events associated with elderberry appear to stem from a small 2001 in vitro study published in the journal European Cytokine Network.

Researchers examined the immune effects of Sambucol, a popular line of dietary supplements containing black elderberry extract. They collected blood samples from 12 healthy donors to analyze changes in cytokine production following the application of four different Sambucol products (Barak, V et al. Eur Cytokine Netw. 2001; 12(2): 290-6). 

Cytokines are a broad category of cell signaling molecules that play a variety of roles in the body’s immune system. Some cytokines are inflammatory and can worsen disease, while others act as anti-inflammatory healing agents.

In the Sambucol study, investigators found that the elderberry formulations significantly increased the production of certain proinflammatory cytokines (IL-1B, TNF-alpha, IL-6, IL-8) as compared to LPS (Lipopolysaccharide), a known activator of white blood cells. The greatest cytokine increase occurred in samples treated with the Sambucol Black Elderberry Extract product.

They concluded that, in addition to its antiviral properties, the extract and other elderberry formulas they studied “activate the healthy immune system by increasing inflammatory cytokine production.” In essence, they showed that elderberry enhanced cytokine production during a natural inflammatory process that arguably benefits individuals who are free from disease.

The authors, based at the Hadassah University Hospital in Jerusalem, proposed that “Sambucol could also have an immunoprotective or immunostimulatory effect” that might benefit immunodepressed patients with conditions like cancer or AIDS. They called for additional research to confirm their preliminary findings through future investigations in vitro, in vivo, and in clinical trials.

Coronavirus Contraindication?

Some have interpreted this Sambucol study as evidence that elderberry provokes the overproduction of proinflammatory molecules, initiating a so-called cytokine storm.

But while the study does suggest that elderberry may increase cytokine production in healthy patients, it does not provide any indication that the herb stimulates hyperinflammation in patients with underlying immune conditions.

With regard to COVID-19, there is mounting evidence that a subgroup of patients with severe COVID-19 also exhibit symptoms of cytokine storm syndrome (Mehta, P et al. Lancet. 2020; 395(10229): 1033-4). Uncontrolled cytokine production can cause major damage to the lung tissue, which is potentially life-threatening.

The excessive immune response that characterizes cytokine storms is not, however, unique to COVID-19, nor to respiratory illnesses in general. Cytokine storms have been identified in a wide variety of both infectious and noninfectious diseases (Tisoncik, J et al. Microbiol Mol Biol Rev. 2012; 76(1): 16–32). They can occur in viral as well as bacterial infections, or as a side effect of medical treatments like cancer immunotherapy. 

There is no evidence that elderberry triggers cytokine storms in people infected with SARS-CoV-2–no one has as yet studied this question prospectively. But some clinicians have argued that it is not a risk worth taking. Treating patients with, or at risk for, CRS with something capable of causing increased cytokine release would obviously be counterproductive.

 A COVID-19 announcement from the University of Arizona Andrew Weil Center for Integrative Medicine explains that because it amplifies the release of certain proinflammatory cytokines––particularly IL-1B, which also increases during the body’s immune reaction to the coronavirus and can cause acute respiratory distress––it is possible that elderberry remedies “could aggravate the inflammatory ‘cytokine storm’ associated with the more severe COVID-19 infections.”

The group therefore recommends to “stop elderberry at the first signs of infection (fever, cough, sore throat) and/or if you test positive for the virus.”

That said, the Weil Center also acknowledges that for prevention of viral illnesses in general, elderberry remains a good choice. “Elderberry extracts may help to prevent the early stage of coronavirus infections, which includes COVID-19,” its guidelines explain, noting that elderberry contains compounds that make it harder for viruses to infect human cells.

Moreover, there is even some evidence that elderberries could have an anti-cytokine effect. In contradiction to claims that it causes cytokine storms, a 2016 study showed that an herbal preparation containing black elderberry exhibited pronounced anti-cytokine activity in patients with vascular disease. The formula successfully slowed the progression of atherosclerosis by inducing a “clinical anti-inflammatory effect, comparable to that of the…NSAIDs” widely used in clinical practice (Kirichenkoa, T et al. Phytomed. 2016; 23(11): 1198-1210).

A research group based at MIT is currently investigating a possible strategy for treating coronavirus and other infections using antibody-like receptor proteins that can bind to and remove harmful cytokines. The team designed a group of water-soluble proteins that mimic six different cytokine receptors in the body and can attach to inflammatory cytokines like interferon and interleukin. They expect to show in forthcoming human studies that the proteins can travel through the bloodstream and soak up excess cytokines, minimizing the havoc that cytokine storms cause in patients at risk of hyperinflammation. 

To date, there are still no proven treatments for COVID-19. With so little known about the potential of elderberry and many other medicinal herbs, it is wise to maintain both an open mind and good critical thinking.

 

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