Kawasaki Disease, ACE-2 & COVID-19: what a pediatrician wants you to know

By now, many of you have heard that the UK has issued an “urgent alert” to all British physicians about a rare complication being seen in children called Kawasaki disease (1) – likely linked to COVID-19, upending our previous thoughts that children are “immune” to serious COVID-19 disease. Similar reports have come out of Italy and Spain.

There are increasing reports of other “non-classic” presentations of COVID-19 in children, including “Covid-toe” and hallucinations. And as I look back over the last month, I’ve seen ALL of these. My son with auditory and visual hallucinations (who ended up needing oxygen for 2 days in the hospital), 3 boys with swollen, bruised, “blood spots” (known as petechiae and purpura) on their toes, and 1 boy with Kawasaki disease. ALL of these boys tested NEGATIVE on nasal PCR swabs for COVID-19, but the UCSF specialists (and I) are convinced ALL of these results are false negatives. 

So, what do I think is going on?

For the answer to that, we need to look more closely at how SARS-CoV-2 invades our cells.

How SARS-CoV-2 Invades

The SARS-CoV-2 virus has spike-like projections that look like crowns (hence the name “Corona-virus” for the Latin word “Corona” which means crown). These spike proteins bind to an enzyme called Angiotensin-Converting Enzyme 2 (ACE2), and once attached, the genetic material of SARS-CoV-2 (called RNA) gains entry into our cells. Viruses can’t replicate on their own, so SARS-CoV-2 hijacks our own cellular machinery to make more copies of itself. These copies are then released into our bloodstream to find other cells with ACE2 receptors to invade. 

Here’s where it gets fascinating. The location of ACE2 in our body explains exactly why there are so many varied symptoms associated with SARS-CoV-2. It’s not that SARS-CoV-2 is randomly attacking ALL cells – it’s attacking those cells that have ACE2 attached to their cell membranes. 

And guess where ACE2 is located?

ACE2 is attached to cells in our: 

• Lungs
• Small intestine
• Brain (cerebral cortex, striatum, hypothalamus, brainstem)
• Blood vessels (veins, arteries, capillaries)
• Heart
• Kidneys
• Blood vessels in our skin
• NOT so much in our nasopharynx (maybe the reason for so many false negatives from nasopharyngeal PCR swabs?

This explains the respiratory, gastrointestinal, neuropsychiatric, cardiovascular, renal and dermatologic symptoms of COVID-19 – even the Kawasaki disease.

Kawasaki disease is a disorder characterized by inflammation of medium-sized arteries in various parts of the body. It can present clinically as prolonged high fever, red eyes, sore throat, swollen lymph nodes in the neck, swollen red palms and soles which eventually peel, vomiting, diarrhea, abdominal pain, and most worrisome – inflammation of the arteries of the heart which can lead to coronary artery aneurysm (bulging of the walls of the artery) with serious complications. We still don’t know yet exactly what causes Kawasaki disease, but it has been linked to various viruses, bacteria, chemical exposures, and now – COVID-19. 

So should all of us parents be freaking out now?

NO!

Knowledge is power. And here’s where knowing more about ACE2 can help us understand from a functional medicine standpoint how to protect our kids from serious complications of COVID-19. 

Serum ACE2 as a “Decoy”

ACE2 has gotten a bad rap these days, I think undeservedly. Initial concerns that medicines that block Angiotensin-converting enzyme (ACE inhibitors) and angiotensin II receptor blockers (ARBs) and INCREASE circulating levels of ACE2 could potentially worsen COVID-19 have been unfounded. No worsening of outcomes has been found with patients who are on ACE inhibitors and ARBs. And a recent study showed the exact opposite – that patients with high blood pressure hospitalized with COVID-19 who were on ACE inhibitors or ARBs had a 63% LOWER mortality risk than those who were not. (2) Current recommendations from cardiologists are that if you are on an ACE inhibitor or ARB for hypertension, to stay on it if you get COVID-19. 

We need to understand the difference between:

1. ACE2 attached to cell membranes (aka membrane-bound ACE2 or ACE2 receptors), and
2. ACE2 that is floating around our blood (aka soluble or circulating serum ACE2)

We may not want more ACE2 attached to our cell membranes, as this could theoretically increase the number of entry portals for SARS-CoV-2 to enter our cells. 

BUT, we probably DO want more circulating serum ACE2. Circulating serum ACE2 may actually act as a “decoy” for SARS-CoV-2 to bind the virus BEFORE it can attach to our cells and invade. Circulating ACE2 is PROTECTIVE against lung injury, septic shock and many of the chronic conditions that increase risk of serious COVID-19 infection in the first place. 

Administering soluble ACE2 has been found to be protective in animal models of acute lung injury (ARDS) and sepsis. One mouse study (3) of acute lung injury and sepsis, that mimicked what is seen in human SARS coronavirus cases, found that lower serum ACE2 worsened acute lung injury, while higher ACE2 actually protected lungs. Another mouse study (4) of acute respiratory distress syndrome (ARDS) induced by avian influenza H5N1 (aka “bird flu”) found that ACE2 administration could improve lung function and survival rates. ACE2 inactivates Angiotensin II. Elevated serum levels of Angiotensin II were found in patients with H7N9 avian influenza, with higher levels of Angiotensin II correlating with worse disease severity and outcome. The authors speculate that treatment with soluble ACE2 could be beneficial for patients with SARS-CoV-1, which is very similar to the currently circulating SARS-CoV-2 that causes COVID-19.

And even more importantly, this study found that administering soluble human ACE2 could actually inhibit SARS-CoV-2 infections in vitro by a factor of 1,000-5,000. (5) 

That’s a LOT of virus being stopped! 

This diagram from the study demonstrates on the left how SARS-CoV-2  enters cells via ACE2 attached to cell membranes (“membrane-bound ACE2”), which can then multiply and release further coronavirus particles. On the right, we see that free-floating human recombinant soluble ACE2 circulating in our bloodstream (“hsrACE2”) can bind to SARS-CoV-2 BEFORE it can attach to membrane-bound ACE2, to prevent it from entering our cells in the first place, therefore reducing our total viral load, which would significantly reduce how many other cells get infected. 

Lower number of infected cells = fewer complications (including Kawasaki disease). 

How to Increase Serum ACE2

One theory behind why children in general still seem to have milder COVID-19 disease than adults is that children tend to have higher levels of ACE2 than adults. Most of us aren’t going to have access to human recombinant soluble ACE2 if we get sick. And ideally, we would have higher levels of serum ACE2 BEFORE we got sick with COVID-19 to stop as much SARS-CoV-2 from multiplying as possible. What if we could increase our baseline serum ACE2 to reduce the risk of serious complications in us and our kids – including Kawasaki disease?

Are there ways to increase our circulating levels of ACE2 naturally?

YES!!!

Here are the Top 5 Ways to Increase your Serum ACE2:

• Regular aerobic exercise can increase ACE2, so be sure to MOVE your body every day! Both High-Intensity Interval Exercise and Moderate-Intensity Continuous Exercise have been shown to increase circulating ACE2 (6), so you don’t have to overdo it. And better yet – make it a family affair. Increase baseline serum ACE2 for the whole family!

• Melatonin can increase ACE2 levels (7). Speculation has also been raised that perhaps children in general do better than adults because they tend to have higher melatonin levels. Make sleep a PRIORITY!  Melatonin supplementation is actually being investigated as a potential therapeutic agent for COVID-19 (8). Most people know of melatonin as our “sleep hormone,” but did you know that melatonin also protects the brain and lungs; has anti-inflammatory, antioxidant and immune-balancing properties; AND can inhibit the NLRP3 inflammasome and NF-kB pathway implicated in ARDS, sepsis and cytokine storm associated with severe COVID-19 complications? In fact, the day after I started Bodi on melatonin, he quickly turned around, weaned totally off his oxygen, and his brain came back – my Bodi Bear was back! [Listen to my FREE Masterclass replay for more details on the top 3 supplements I believe helped Bodi turn around so quickly!]

• Vitamin D is my #1 all-time favorite immune-boosting nutrient – so important during the flu season and especially now, during the COVID-19 pandemic.  Cathelicidin produced by Vitamin D can neutralize LPS (lipopolysaccharides) that are responsible for so much of the damage that we see in sepsis, and also has antimicrobial and immunomodulatory effects. (9) Vitamin D deficiency may actually be considered a risk factor for sepsis and inflammatory disorders, and a new study finds a direct link between vitamin D levels and severity of COVID-19 disease (10). In this study, 86% of people with normal vitamin D levels had mild COVID-19 disease; on the other hand, 73% of people with low vitamin D levels had severe or critical COVID-19 disease. The authors conclude:
  “This means that serum (OH)D level in the body could account for the clinical outcomes of the patients infected with Covid-2019. An increase in serum (OH)D level in the body could either improve clinical outcomes or mitigate worst (severe to critical) outcomes. On the other hand, a decrease in serum (OH)D level in the body could worsen clinical outcomes of Covid-2019.”
  Vitamin D deficiency is one of the most common nutrient deficiencies in children and adults. See my article A Pediatrician’s Pandemic Immune Support Plan for more guidance on getting in those Vitamin D-rich foods and potential supplementation dosages.

• Vitamin A has amazing antioxidant and antiviral properties, and can increase ACE2 expression (11).  As far back as 1928, vitamin A was known as the “anti-infective” vitamin (12). In fact, in regions where vitamin A deficiency may be present, the World Health Organization (WHO) recommends a 2-day high-dose vitamin A protocol to treat measles (13). Vitamin A is found in all those yummy, red-orange fruits and veggies. See my article A Pediatrician’s Pandemic Immune Support Plan for more ideas for Vitamin A-rich foods and possible supplementation dosages. 

• Curcumin is one of my favorite anti-inflammatory nutrients found in turmeric – think yummy Indian curries and golden lattes. Turmeric has caffeic acid (NOT related to caffeine), which was the active component in Sambucus Formosana Nakai (similar to Sambucus nigra or black elderberry) found to significantly inhibit replication and block attachment of another human coronavirus, HCoV-NL63 (14). Curcumin was also found to increase ACE2 and protect kidney function (15) – even more reason to believe that curcumin may be beneficial in protecting against serious COVID-19 disease. 

Be Prepared When Society Reopens

As society reopens, we will see a surge in new COVID-19 cases, in children and adults. 

Kids are getting sick, and we need to be prepared. As many as 5.7-20% of children with COVID-19 may require hospitalization, and 0.58-2% may need ICU care (16). 

💗 I am NOT telling you this to scare you.💗

💗 I AM telling you this because I firmly believe that KNOWLEDGE IS POWER. And that a functional and integrative medicine approach to the pandemic is essential. 💗

The average length of hospital stay for pediatric COVID-19 is: 14 DAYS

Bodi was hospitalized for: LESS THAN 2 DAYS!

I absolutely believe that an integrative & functional medicine approach made a HUGE difference for Bodi, and that it can for your kids tooThat’s why I taught my free Masterclass: A Holistic Pediatrician’s Guide to the Pandemic that is packed with actionable and practical information to get started on your family’s immune support regimen. And for even more in-depth information as we re-enter society, I created my online program, Integrative & Functional Medicine Strategies for the Pandemic, to teach you everything I know as a holistic pediatrician and mama who’s had 2 kids recover beautifully from COVID-19, so you can:

💥Stay calm.

💥Be prepared. 

Learn more about my program HERE: Integrative & Functional Medicine Strategies for the Pandemic. I’m here to support you and your family. We’re all in this together.

xo Holistic mama doc – Elisa Song, MD 💕

References:

1. https://www.reuters.com/article/us-health-coronavirus-britain-children/uk-says-some-children-have-died-from-syndrome-linked-to-covid-19-idUSKCN22A0XW
2. https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.120.317134
3. https://www.nature.com/articles/nature03712
4. https://www.nature.com/articles/ncomms4594
5. https://www.sciencedirect.com/science/article/pii/S0092867420303998
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970173/
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016897/
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102583/
9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253453/
10. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3571484
11. https://www.ahajournals.org/doi/10.1161/01.HYP.0000146400.57221.74
12. https://www.ncbi.nlm.nih.gov/pubmed/15189121

13. https://pubmed.ncbi.nlm.nih.gov/11869601/
14. https://pubmed.ncbi.nlm.nih.gov/31560964/
15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153927/
16. https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e4.htm

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