COVID-19 Elderberry & Cytokines

We are so pleased to have Lindsey Wells, ND, join in our series of Q&As on COVID-19. Her focus in this interview will be on Elderberry and Cytokines.

Dr. Lindsey Wells is a naturopathic physician. Dr. Wells has focused her practice on pediatric primary care and consultative care for Autism Spectrum Disorder (ASD), PANS/PANDAS, other neurodevelopmental disorders, and various chronic illnesses. She uses therapies, including homeopathy, botanical medicine, nutraceuticals, nutrition, counseling, and water therapy. This model of care addresses the biochemical, nutritional, and energetic needs of each patient to improve overall health. For her complete bio and more information, please see her website: https://lindseywellsnd.com.

Please Note: Coronavirus disease (COVID-19) is a new strain that was discovered in 2019 and has not been previously identified in humans. The WHO is closely monitoring and updating the information regularly. Recommendations regarding prevention and treatment will change and evolve as more data is processed. It is essential to communicate with your Primary Care Provider (PCP) directly regarding you and your family’s unique healthcare needs. https://www.who.int/emergencies/diseases/novel-coronavirus-2019

Gabriella: So let’s start with the basics first. What are the most common symptoms of COVID-19?

Lindsey: 

Most Common Symptoms

• Fever
• Cough
• Shortness of Breath 

Other Symptoms

• Aches and Pains
• Sore Throat
• Fatigue
• GI Symptoms 
• Losing Sense of Smell OR overpowered with a sense of smell

Emergency Warning Signs to seek immediate medical attention:

• Trouble Breathing
• Persistent Pain or Pressure in the Chest
• New Confusion or Inability to Arouse
• Bluish Lips or Face

Source: https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html

Gabriella: What is the medical community seeing in terms of children and COVID-19?

Lindsey:

• Children do not appear to be at higher risk for COVID-19 as adults 
• Children generally presented with milder symptoms 
• Symptoms will include “cold-like” symptoms such as fever, runny nose, cough, vomiting, and diarrhea

Reuters Article by Gene Emery on March 17, 2020, recapped a couple of studies from China.

• 745 Children 2months to 15 years old, only 1.3% were found to be infected. Overall they had milder symptoms.
• In the small study, 7 out of 10 kids had a fever didn’t go above 102.2
  • None had pneumonia
  • Headaches, vomiting, labored breathing, headache, fatigue that are seen adults were not seen in these kids
  • Half had a cough. 4 had a sore throat, 3 had diarrhea, 2 had nasal congestion
  • 8 kids still came back positive in rectal swabs after they no longer were positive in nasal swabs. So rectal swabs could be more accurate in children. 

Gabriella: All right, let’s delve into cytokine. Will you please explain what a cytokine is? Is there only one kind of cytokine?

Lindsey: Cytokines are small, secreted proteins released by cells. They have a specific effect on the interactions and communications between cells that mediate and regulate the immune system and inflammation. In essence, they are chemical messengers that are released to help regulate the immune system response. With that immune system response comes inflammation. The immune system is supposed to recognize something that should not be there, and it calls all of its armies to that site to help fight inflammation. Part of its army is cytokines.

Gabriella: So are all cytokines, in simple terms, bad?

Lindsey: No, not all. There are both pro-inflammatory cytokines and anti-inflammatory cytokines.

• Pro-inflammatory cytokines: IL-1β, IL-6, and TNF-α
• Anti-inflammatory cytokines: interleukin (IL)-1 receptor antagonist, IL-4, IL-10, IL-11, IL-13, IL-19, IL-35

We need pro-inflammatory cytokines when we are sick. The body commonly releases pro-inflammatory proteins in response to a viral infection. This results in the recruitment of immune system cells to the site of infection. So the body releases these pro-inflammatory cytokines in response to a viral infection which recruits the immune cells to that site of infection to help fight the illness. 

Source: Zhang, Jun-Ming, and Jianxiong An. “Cytokines, inflammation, and pain.” International anesthesiology clinics vol. 45,2 (2007): 27-37. doi:10.1097/AIA.0b013e318034194e

Gabriella: Then, what is a cytokine storm? We hear that term used a lot with COVID-19 and often with our kids with PANS/PANDAS.

Lindsey: A cytokine storm is an overproduction of immune cells and cytokines, which, in a flu infection, is often associated with a surge of activated immune cells like into the lungs. So if you have these activated immune cells and so many of them causing this storm is that it can lead to septic shock or organ failure. 

Source: Tisoncik, Jennifer R et al. “Into the eye of the cytokine storm.” Microbiology and molecular biology reviews: MMBR vol. 76,1 (2012): 16-32. doi:10.1128/MMBR.05015-11

Gabriella: Does everyone with COVID-19 have a cytokine storm? How are they related?

Lindsey: As far as we know, not all patients. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome.

Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognized, hyperinflammatory syndrome characterized by a severe and sudden onset and fatal hypercytokinemia, which means more cytokines are coming to that area, with multi-organ failure. In adults, sHLH is most commonly triggered by viral infections. Hypercytokinemia is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and immune cells, with highly elevated levels of various cytokines.

• Cardinal features of sHLH include unremitting fever, elevated cytokines, and elevated ferritin; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. (This is seen in COVID-19)
• A cytokine profile resembling sHLH, (the severe cases) ` is associated with COVID-19 disease severity, characterized by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α.
  • This is a subgroup of people with severe COVID-19. Still, more research is coming out, but a cytokine storm is not happening in every single person.

Source: Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506

Gabriella: What is elderberry? Is elderberry an immunomodulator?

Lindsey: The botanical name for Elderberry is Sambucus nigra, and it is known for its anti-viral properties against the flu and common cold. It is a commonly used botanical. Yes, elderberry is an immunomodulator.

• Elderberry inhibits the haemagglutination of the influenza virus to prevent adhesion of the virus to the cell receptors, meaning it doesn’t allow the flu virus to adhere to the cell-receptors, which is how it helps to prevent viral replication.
• It also has anthocyanins, which are anti-inflammatory in their properties, which is why it can help with aches, pain, and fever seen in acute illness.
• It is an immunomodulator. If your immune system is too overstimulated, it can help to decrease that stimulation in the body. If it is understimulated, it can help to increase it. This is an important part of the conversation about elderberry as it modulates the immune response; it does not necessarily cause everyone to enhance their immune system and enhance those cytokines.

Gabriella: There has been discussion that elderberry can cause a cytokine storm. Please address the facts.

Lindsey:  There are many studies done on elderberry; I am going to go over a few of them so that you can reference them.

Study 1: Sambucus nigra extracts inhibit infectious bronchitis virus at an early point during replication

Background: This study looked at the Infectious Bronchitis Virus (IBV), a pathogenic chicken coronavirus that infects the respiratory tract of chickens and causes the production of eggs with deformed and weakened shells. There is an IBV vaccine, but it is not wholly effective in protecting against new infections due to the recombinant nature of the virus i.e., the virus can replicate and mutate. 

The study looked at 3 extracts of botanicals that have anti-viral properties due to polyphenol properties. The 3 plant extracts were Rhodiola, Nigella sativa seeds, and Sambucus nigra (elderberry. 

Results:

• Treatment with elderberry reduced viral titers by 4-6 orders of magnitude – significant
• Virions (an infective form of a virus outside a host cell) treated with elderberry shows compromised envelopes and presence of membrane vesicles, i.e. it disrupted the envelope and membrane of the virus so that it was deemed ineffective and could not replicate.

Conclusions:

• Vaccination against IBV in conjunction with administering elderberry due to active polyphenols could have a synergistic effect 
• As stated in this study, the results of this study could potentially translate to other coronaviruses, including those that affect humans

Source: Chen, C., Zuckerman, D.M., Brantley, S. et al. Sambucus nigra extracts inhibit infectious bronchitis virus at an early point during replication. BMC Vet Res 10, 24 (2014). https://doi.org/10.1186/1746-6148-10-24

Study 2: Randomized Study of the Efficacy and Safety of Oral Elderberry Extract in the Treatment of Influenza A and B Virus Infections

Background: The study took sixty patients (aged 18-54 years) who were suffering from influenza-like symptoms for 48 hours or less. The subjects were treated with elderberry for four times a day for five days. The first dose was given within 48 hours of the onset of symptoms. It was a randomized, double-blind, placebo-controlled study during the influenza season of 1999-2000. The subjects scored their improvements daily on a scale of 0-10 (0 = no improvement; 10 = pronounced improvement).

Results: 

• In the treatment group, a pronounced improvement was reached after 3-4 days compared to 7-8 days in the control group who were not treated with elderberry. The elderberry did shorten the duration of the illness. 
• The treatment group used rescue medications (nasal spray and painkillers included) significantly less compared to the placebo group. 

Source: Zakay-Rones, Z., Thom, E., Wollan, T., & Wadstein, J. (2004). Randomized Study of the Efficacy and Safety of Oral Elderberry Extract in the Treatment of Influenza A and B Virus Infections. Journal of International Medical Research, 132–140. https://doi.org/10.1177/147323000403200205

Study 3: Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama

Background: This trial was a placebo, double-blind study conducted on a group of individuals living in a kibbutz during the outbreak of influenza B in 1993. They used elderberry as a means of treatment in the treatment group and fever, improvement in symptoms, and complete cure found in 6 days. 

Results:

• Fever was resolved in 93% of the cases in 2 days compared to 6 days in the control group
• Complete resolution of symptoms seen in 2-3 days in 90% of the treatment group compared to 6 days in the placebo group
• There were higher hemagglutination (the clumping together of red blood cells ) inhibition titers to influenza B in the group treated with the elderberry compared to the control. 

Source: Zakay-Rones, Zichria et al. “Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama.” Journal of alternative and complementary medicine 1 4 (1995): 361-9. DOI: 10.1089/acm.1995.1.361

Study 4: Elderberry Supplementation Reduces Cold Duration and Symptoms in Air-Travelers: A Randomized, Double-Blind Placebo-Controlled Clinical Trial

Background: A larger-scale double-blind controlled trial with 312 air travelers. The study was designed so that participants took either the elderberry or placebo for 10 days before travel and 5 days after travel. They recorded symptoms at baseline (10 days before travel), before travel at 2 days, and after travel for 4-5 days. As well as recording cold symptoms in a daily diary.

Results: 

• Elderberry group had a significantly lower number of cold episode days as a collective group (57 days) compared to the placebo group (117 days)
• Elderberry group had lower symptom score (247) compared to the placebo group (583)
• Elderberry group experienced 2-day shorter duration of cold

Source: Tiralongo, Evelin et al. “Elderberry Supplementation Reduces Cold Duration and Symptoms in Air-Travellers: A Randomized, Double-Blind Placebo-Controlled Clinical Trial.” Nutrients vol. 8,4 182. 24 Mar. 2016, doi:10.3390/nu8040182

Gabriella: Do any of those studies talk about cytokine storms?

Lindsey: No, they don’t. There are ZERO studies on PubMed about Elderberry and Cytokine Storms. Concerns about elderberry and cytokines seem to be from a study done in 2001 on healthy individuals. 

Study 5: The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines

Background: This study looked at using elderberry and production of cytokines in healthy individuals, so people who did not have any symptoms. They then used the elderberry to monitor and measure specific inflammatory cytokines. 

Remember, you always have to look at the study design. This study was very specific about only measuring those inflammatory cytokines we talked about in the beginning. 

Results:

• In this study, researchers concluded, “Sambucol might, therefore, be beneficial to the immune system activation and in the inflammatory process in healthy individuals.”
• The key takeaway from this study is that Elderberry supported cytokine production during a healthy inflammatory process related to the optimal immune function that was beneficial in this situation. It said it did produce an inflammatory or cytokine response, but it was beneficial and optimal for that certain situation.
• The research DID NOT suggest it would stimulate a cytokine storm in patients that have an underlying condition that may tax the immune system. 
• So what you are seeing about elderberry and cytokine stimulation is based on this study from 2001. They did not measure the pro-inflammatory cytokines. 

Source: V. Barak, T. Halperin, I. Kalickman. The effect of Sambucol, a black elderberry-based natural product, on the production of human cytokines: I. Inflammatory cytokines. European Cytokine Network. 2001;12(2):290-6. PMID: 11399518

Gabriella: So, with the knowledge, you have right now on the use of elderberry for other viruses and what you know about COVID-19, what are your thoughts on taking elderberry now?

Lindsey: 

• Elderberry is not likely to cause a cytokine storm.
• It should be used as immune support and prevention. Plenty of human and animal trials show how elderberry works. The properties in elderberry help with flu and cold symptoms.
• Although elderberry is safe, to err on the side of caution, if you have symptoms of COVID-19, then DISCONTINUE the use of elderberry. 

Gabriella: Thank you, Dr. Wells. This provided us with clarity on this matter. We appreciate that you took time out of your busy day to speak with ASPIRE!

Dr. Lindsey wells and her colleagues at New England Center for Health are continuing to host a series of zoom calls on COVID-19. The schedule will be updated weekly.