Why COVID-19 is serious for some people, while most people get a cold, or no symptoms.
There is an important connection between ACE-inhibitor medication for hypertension and COVID-19 that explains why there are so many deaths among those infected with COVID-19, even from a simple co-morbidity of hypertension, why the African-American community is more affected, why people become re-infected, and why viral infection is asymptomatic or very mild in almost everybody else.
Centro Hospitalar de Vila Nova de Gaia/Espinho
- "some data may even suggest that viral load is not related to disease severity, so maybe ACE2 expression isn't the issue here, but rather some other mechanism (such as bradykinase-bradykinin balance)"
"Angiotensin converting enzyme (ACE) inhibitors inhibits not only the convention of angiotensin II from angiotensin I, but also the bradykinase that degrades bradykinin. As bradykinin is generally pro-inflammatory or an inflammatory mediator, whether the use of ACEI may worsen the symptoms during Covid-19 infection has to be considered."
“I would certainly stop ACE-I’s in any patient acutely admitted to the hospital with COVID.” Josh Farkas, M.D., Professor of Pulmonary and Critical Care Medicine
https://www.researchgate.net/post/COVID-19_and_angiotensin-converting_enzyme_inhibitros
https://emcrit.org/pulmcrit/covid19/
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"EPIDEMIC LINKED TO ACE-INHIBITORS": TWO SCENARIOS
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PRE-COVID-19
If someone went to an emergency dept. with a dry cough, headache, fever, dizziness, loss of taste, and trouble breathing, and was taking angiotensin converting enzyme-inhibitors, or ACE-inhibitors, for blood pressure, doctors would recognize it as a side effect of the medication. These side effects are caused by swollen airways, called angioedema, due to the build-up of bradykinin. So, they would take the person off of the ACE-I, as the prescription instructions direct, and put him or her on Losartan, an ARB (angiotensin receptor-blocker). ARB’s (like losartan), block the angiotensin receptor. So, ARB’s act in a completely different way from ACE-inhibitors, and do not cause a build-up of bradykinin, or a dry cough, or angioedema. This is why, when people develop these side effects of ACE-I’s, they are switched to an ARB, and they no longer have a cough or swollen airways. This practice, along with other therapies as needed, such as a ventilator, would eventually resolve these symptoms. These side effects would be most likely if the person was an African-American, who are most susceptible to the side effect of swollen airways and also have more hypertension than other ethnicities.
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POST-COVID-19
Now, if someone goes to an emergency dept. with the same symptoms, and is taking ACE-inhibitors, they don’t take the person off of the ACE-I and, instead, test for the virus, which has the exact same symptoms. Then, if the patient tests positively, he or she remains on their ACE-I, and may be put on a ventilator, but many die. According to the American Heart Association, they keep patients on their ACE-I to protect their heart from “cardiac injury”. However, “in drug induced non-allergic angioedema, symptoms resolve only after drug discontinuation”. Angioedema, which is the "unusual pneumonia" that many of the patients die from, is caused by the build-up of bradykinin, which occurs in both the virus and with ACE-inhibitors.
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Regarding bradykinin: “Researchers at the Radboud university medical center (Nijmegen, the Netherlands) seem to have found an essential mechanism in the disease process of COVID-19, which has so far been overlooked. Bradykinin, which makes blood vessels leak, might be the missing link. When the virus is introduced, ACE2 receptors disappear from the lung cells, giving bradykinin free rein in causing the small blood vessels to leak massively at the site of infection. That leakage causes lung problems because they partly fill up.” April 11
EXCESS DEATHS FROM REMAINING ON ACE-INHIBITORS IN THE HOSPITAL WITH COVID-19
There are other conditions, besides being on ACE-inhibitors, which cause a tendency for angioedema and, thus, the excessive reactivity to the virus. Once having had this side effect from ACE-inhibitors increases the risk of angioedema from losartan. Also, smoking and taking hormonal contraceptives both deplete zinc, and they can cause angioedema as well. But, in a study entitled "Risk factors associated with severe and recurrent angioedema: an epidemic linked to ACE-inhibitors", the authors state, "The most common cause of angioedema was angiotensin converting enzyme inhibitor (ACEi)-induced (496 [56.6%])." So, it's critical to focus on these drugs to reduce the excessive number of severe cases and deaths in the current "epidemic".
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In the hospital, continuing the ACE-inhibitor would prolong, rather than decrease, time on a ventilator, as angioedema would continue to increase, and longer time on a ventilator increases the possibility of organ failure and death. It also renders these people more vulnerable to another episode of COVID-19, or “re-infection”, which is, unusually, occurring with COVID-19. Furthermore, the Wuhan study of 89 fatalities, published on April 3, found that respiratory failure was the cause of death for 94%, so cardiac injury may play a small part in increased fatalities. Also noted in this study was that, unusually, hypertension alone was a common comorbidity with fatalities, with a total of 68% having comorbidities that would have included blood pressure medication such as ACE-inhibitors. Similarly, in Italy, over half of those who died were taking either ACE-inhibitors or ARBS (angiotensin receptor blockers) like losartan. So, it might be extremely important to treat a COVID-19 patient who is taking an ACE-I as they would if they were also having the serious side effect of their medication, which they apparently are, and immediately take them off of it, so as not to increase the side effect of angioedema, even if they test positive for the virus. Also, these are the prescribing instructions that have been approved by the FDA for this drug.
Another way to lower the excess serious cases and fatalities from COVID-19 would be to go back to the pre-2018 definition of hypertension, which would take many millions of Americans off of ACE-I's and out of increased danger from the virus, including many younger people, including children. Any harmful effect of this would presumably be small since Germany and South Korea, the countries with the least COVID-19 deaths, never changed their guidelines (thus, they also have a low percentage of people on ACE-inhibitors). Another point was made regarding people over age 70. Treatment goal is now BP between 130 and 140, which often requires a high dose of the drug, thus more side effects, plus "some studies suggest that BP has limited predictive value for total mortality after the age of 70 years". Finally, as many people as possible could be switched to another blood pressure medication, as soon as that is feasible.
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THE ACE2 THEORY: BOTH ACE-I'S AND ARB'S MIGHT INCREASE VIRAL ENTRY, SO BOTH ARE A PROBLEM
The virus gains entry via ACE2, which is part of the angiotensin system, and both ACE-I's and ARB's cause an increase in ACE-2. So, there is much interest in this point. But, as a result of this theory, all articles and studies addressing COVID-19 lump ACE-I's and ARB's together, as if all their effects are similar. Yet, ACE-I’s cause the same symptoms as the virus, but ARB’s protect against them. So, in effect, they could hardly be more different. Furthermore, a small study found that African Americans have far less ACE2 than Chinese, yet Chinese Americans haven’t been affected very much, while African Americans have been very affected. Not surprisingly, then, this theory has been widely criticized, and thus appears to be incorrect. However, researchers continue to just test this theory, and study ACE-I's and ARBS together as the same medication. Instead, we need to focus on the actions and side effects of ACE-I's, in order to generate useful data on this problem.
WHAT DOCTORS ARE SAYING (a sample):
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Comments on an April 1 article by the American College of Cardiologists and the American Heart Association stating to not stop giving COVID-19 patients ACE-inhibitors.
Dr. William DeMedio-This article says don’t stop ACEI Or ARB (losartan) meds in people with CoV19, but the science is not settled. I want to see if SARS outcomes are improved or impaired by these meds; or no net change. There is more than one way to lower BP for the short term in these people. How about a study switching some to a different class of antihypertensive, eg CCB or even a PDE 5 inhibitor? We could compare rate of SARS and death. ACE inhibitors increase pulmonary inflammation. That is why some people cough on them. Some studies suggest they may be associated with lung cancer. I do not think they are fully exonerated yet. This needs more work for an answer.
Dr. Wayne Greaves
@Dr. William DeMedio I am concerned that recommendations are being made on so little data and such limited concern. As a HCW myself I am unsure what to do. The data from Italy is very troubling with pre-hospital use of 36% ACEIs and 16% ARBs (losartan) among Covid-19 persons that died. I sure hope someone is looking carefully at the emerging US data as the cases increase so we can have an answer based on more robust data. On another note, some have suggested at least for those on ACEIs which tend to increase bradykinin and thereby pro-inflammatory response that Vitamin D levels should be checked proactively and those with low levels be given Vit D to decrease inflammation in those who are at risk of pneumonia/ARDS.
Dr. STEPHEN ALGEO-Now with reports that in the US African American patients are recording worse outcomes with Covid-19 you have to wonder whether racial differences in ACE metabolism/physiology are a factor. As a cardiologist I am aware that African-Americans do not respond as well to ACE-inhibitors when used for both hypertension and CHF as other groups.
Dr. Francine Moring-ACE inhibitors block zinc. Zinc is needed in T cells. It helps decrease viral replication. Hydroxychloroquine acts like an ionophore, allowing zinc to get into cells.
https://www.medscape.com/viewarticle/927952 Click on "Comments"
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Dr. Fauci, from a March 18 interview, focuses just on ACE-inhibitors as the potential problem:
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HB: Another clinical issue that really come up the last few days is this issue about ACE and ARBs in individuals who are either on them or develop disease. Now the Heart Failure Society of America, ACC, and AHA just came out with a statement yesterday. I don't know how familiar you are with the question, Tony, but I'll let you comment.
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AF: Well, I am quite familiar with the question. So, here's the issue -- and this is something that I take a little bit more seriously about we really need to get data and we need to get data fast. In Italy, 99% of the people who died had an underlying condition, that's not surprising. However, when they broke down the underlying conditions, 75% of it was hypertension, which was, to me, a bit of a red flag, because Italy is a very developed country. And I would imagine, if you knew the patient had hypertension, then the patient, almost certainly, had a physician. And that physician almost certainly treated the person for their hypertension. If 75% of those so-called underlying conditions was hypertension, and the hypertension was well-controlled, why should someone who has hypertension that's well controlled have a much greater chance of dying than somebody else with any other kind of underlying condition? I mean I look upon someone who has well-controlled hypertension and nothing else wrong with them as a reasonably healthy person, yet it was skewed towards people with hypertension, which tells me somebody better look really carefully at this issue, and that's what we're hopefully going to get that data from the Italian scientists.
https://edhub.ama-assn.org/jn-learning/audio-player/18324686
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The following is a series of studies and articles describing:
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The action of ACE-inhibitors and its side effects, plus the large number of African Americans taking ACE-I's.
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Symptoms of COVID-19 are the same as side effects of ACE-inhibitors, again from bradykinin, so people taking ACE-inhibitors would have a magnified effect of symptoms if they become infected.
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Unlike with other viruses, people often become “re-infected”. This doesn’t make sense normally, but it does make sense if they are still on their ACE-inhibitor, which would again cause an over-reaction, even to a normal cold.
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Prescription guidelines have recently changed, and this may explain how countries differ re: COVID-19 serious cases and fatalities, together with ACE-inhibitor prescriptions.
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Official position of CDC and medical community: no one should stop taking ACE-inhibitors, even if infected with COVID-19 (as explained by an Astrazeneca spokesperson, Dr. Lavie, who doesn’t admit that he’s an Astrazeneca spokesperson. Notably, Dr. Lavie no longer prescribes them to his own patients because of the side effects!).
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What to do about the problem.
1.The action of ACE-inhibitors and its side effects: dry cough, dizziness, nausea, headache, loss of taste (from zinc deficiency), fever, and angioedema (swollen airways). The symptoms are due to increased bradykinin (bradykinin is normally broken down by ACE-angiotensin-converting enzyme, which is a zinc enzyme). African-Americans are far more prone to this side effect, plus they have the most hypertension, of any other ethnic group. Since the change in guidelines in 2018, there was a major campaign to get African Americans on hypertension meds. ACE-inhibitors are very widely prescribed for hypertension as it's the front-line medication, especially for diabetes, plus it's very inexpensive-about $3 per month, so a large percentage of African Americans are taking this drug, despite their increased risk for side effects. ACE-I’s have also caused liver injury, even “sudden onset of hepatic injury after years of safe use.” These symptoms resolve only after discontinuation of the drug.
https://edhub.ama-assn.org/jn-learning/audio-player/18324686
https://www.ncbi.nlm.nih.gov/pubmed/11827930
https://cvpharmacology.com/vasodilator/ACE
https://www.ncbi.nlm.nih.gov/pubmed/10893650
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638407/#b10-ptj3803170
https://www.nationaljewish.org/conditions/angioedema
https://www.ncbi.nlm.nih.gov/books/NBK548912/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652893/
2.Symptoms of COVID-19 are the same as side effects of ACE-inhibitors, again from bradykinin, so people taking ACE-inhibitors, who also have an excess of bradykinin, would have an over-reaction to the virus, with a magnified effect of symptoms, if they become infected. Why are they so similar? In an unusual and deadly coincidence, both the virus and ACE-inhibitors are derived from venomous snakes! ACE-inhibitors are derived from the Brazilian pit snake, and the closest animal that the virus most likely has come from is also a venomous snake, perhaps a cobra, before it went to a bat. So, this probably explains why the symptoms are the same. The percentage of people with only hypertension that have died is unusually high, even though, according to Dr. Fauci, hypertension by itself shouldn't increase risk for death from a virus. Thus, it appears that people taking ACE-inhibitors, with their excessive bradykinin, are more sensitive and reactive to the virus, as it too increases bradykinin. So, focusing on lowering use of ACE-inhibitors, especially regarding how this drug is dealt with in the hospitals, would very likely bring down the number of cases and deaths.
Another fact that implicates hypertension medications is that people with type O blood are least likely to get a serious case of COVID-19, even though a greater percentage of Americans are type O than any other blood type. At the same time, people with type O blood have less risk for blood clots, and are less likely to have heart attacks and stroke, so they are less likely to be taking ACE-inhibitors, than other blood types. So, it may be that more people with the other blood types, who get the serious symptoms, are taking these medications.
https://www.preprints.org/manuscript/202004.0023/v1
https://aliveandwellaustin.com/news/what-we-want-you-to-know-about-coronavirus-covid-19/ Ibuprofen augments bradykinin-induced ... - JACI
www.jacionline.org › article › pdf
https://www.ncbi.nlm.nih.gov/pubmed/28935640
https://www.scientificamerican.com/article/snakes-could-be-the-original-source-of-the-new-coronavirus-outbreak-in-china/ https://www.pharmaceutical-journal.com/news-and-analysis/news/from-snake-venom-to-ace-inhibitor-the-discovery-and-rise-of-captopril/10884359.article?firstPass=false
https://www.medrxiv.org/content/10.1101/2020.04.08.20058073v1
3.Unlike with other viruses, people often become “re-infected”, which doesn’t make sense normally. But this does make sense if they are still on their ACE-inhibitor, which has so much to do with the excessive symptoms.
https://www.france24.com/en/20200328-can-the-coronavirus-infect-someone-twice
4.How prescription guidelines recently changed, and how countries differ re: ACE-inhibitor prescriptions. US used new guidelines for prescribing ACE-inhibitors in late 2017, which added 35 million more Americans to the population who could be prescribed hypertension medications, including many younger people, African Americans, and newly prescribed (thus more subject to the side effects). Currently, a whopping 48% of adult Americans have hypertension, according to these guidelines!-and a large percentage of them have been prescribed ACE-inhibitors. Side effects of cough and angioedema, now called viral pneumonia, usually occur within a year after a new prescription. This may explain why the flu season right after the guideline change was especially bad, with far more illnesses, hospitalizations, and deaths from pneumonia, which might reflect the sudden increase in cases of ACE-inhibitor side effects, set off by a viral infection.
https://www.tctmd.com/news/new-european-hypertension-guidelines-not-harmony-us-guidance
https://www.cdc.gov/flu/about/burden-averted/2017-2018.htm#table1
5.Official position of Medical Community: no one should stop taking ACE-inhibitors, even if infected with COVID-19, even though Dr. Fauci stated that this connection should be looked at “very carefully”. Also, Dr. Lavie, a spokesperson for Astrazenec, who has been encouraging people to stay on their ACE-inhibitors, said that he himself had stopped prescribing them to his own patients a year ago, due to the side effects.
https://www.ahajournals.org/doi/10.1161/JAHA.120.016219
https://jamanetwork.com/journals/jama/fullarticle/2763803
https://edhub.ama-assn.org/jn-learning/audio-player/18324686
https://www.youtube.com/watch?v=vsOL3_0Gw3Y
https://www.youtube.com/watch?v=GOyBaAlrWsQ&t=15s
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6.How to lower hospitalizations and deaths:
1.by lowering the number of people on ACEI’s. We could follow the 2017 guidelines, like Germany, Netherlands, and South Korea, which have had less of a problem with the virus. We might also consider going back to the pre-2000 "100 plus your age" guideline for defining high blood pressure, as "clinical trials involving hypertension medication show NO increased lifespan among users when compared to non-users." Also, in men 70 and older, cardiovascular risk, as well as dizziness and falls, may begin to rise if high doses of medication cause systolic blood pressure to dip below 130. There was also no advantage regarding dementia. It may also be relevant that, in the 1970s the target limits for initiating drug treatment was 160/95. In view of all this, the "Space-Doc" Dr. Duane Graveline, M.D. writes, "The Public Citizen's Health Research Group strongly advises consideration of age in determining whether or not treatment is justified, suggesting that in the elderly only pressures equal to or above 180/100 might be treated beneficially with drugs." Although these numbers probably would need to adjusted on an individual basis, given the added problem of COVID-19, this might be very sound advice at this time.
2.by mandatory self-quarantine for those staying on ACEI’s. With the most vulnerable people safe at home, others should freely mingle to ensure herd immunity.
3.by treating hospital cases, for those on ACEI’s, for the ACEI side effect. This would mean immediately taking them off ACEI’s, which is only following the prescription instructions. Also, possibly use Icatibant, which breaks down bradykinin, so it may be effective. This has been used for ACE-I-induced angioedema. ACE normally breaks down bradykinin, but it is low with zinc-deficiency (ACE is a zinc enzyme). ACE-inhibitors lower zinc, as does smoking and oral contraceptives, and all of these increase risk for angioedema. Plaquinil, on the other hand, increases zinc in the cells, so it can be used to treat angioedema.
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4.by a public health campaign that teaches people how to avoid depleting zinc, which increases risk for having a serious case of COVID-19. Notably, zinc deficiency also leads to hypertension. This would include a list of all drugs that deplete zinc, such as ACE-I's, thiazide diuretics, hormonal birth control, smoking, and alcohol, as well as sugar, high fructose corn syrup, refined flour, and caffeine. Also, zinc lozenges supply zinc in the proper 2+ ionic form, so it may be very helpful. As James A. Robb, virologists writes, “Stock up now with zinc lozenges. These lozenges have been proven to be effective in blocking coronavirus (and most other viruses) from multiplying in your throat and nasopharynx. Use as directed several times each day when you begin to feel ANY “cold-like” symptoms beginning. It is best to lie down and let the lozenge dissolve in the back of your throat and nasopharynx.” Other preventative supplements include selenium, lysine, lactoferrin (as a supplement, or in low heat-processed whey protein powder), and arachidonic acid (as a supplement, or in liver and dark poultry meat, pork, lard, bacon, eggs, and dairy fat). A diet that includes these nutrients and prevents hypertension will be explained on the next page, in the near future. Meanwhile, see www.tendler5.wixsite.com/highlysinediet.
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5.by a public health campaign that explains the risk factors for hypertension, many of which are the same substances that deplete zinc, as zinc defiency is one fo the factors leading to hypertension. These include alcohol, prenatal exposure to caffeine (caffeine raises blood pressure by blocking arachidonic acid hormone prostacyclin), prenatal exposure to bisphenol A or other estrogenic chemicals, smoking, lead exposure, hormonal contraceptives, not being breastfed, obesity (excessive sugar and modern oils), and ethnicities: African American and Hispanic.
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https://www.disabled-world.com/health/cardiovascular/hypertension/bp-100-plus-age.php
https://spacedoc.com/articles/blood-pressure-and-heart-disease
https://www.preprints.org/manuscript/202004.0023/v1
https://www.ncbi.nlm.nih.gov/pubmed/11827930
https://doi.org/10.1164/ajrccm-conference.2019.199.1_MeetingAbstracts.A1767
https://link.springer.com/article/10.1186/s13075-018-1774-x
https://www.ncbi.nlm.nih.gov/pubmed/3003288
https://www.uchealth.org/today/zinc-could-help-diminish-extent-of-covid-19/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137820/
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AFTERTHOUGHT
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COVID-19 will be a blessing to Americans if we use it as a long-needed opportunity to improve our diet and limit chemical exposure, so Americans can become healthy again, with a strong immune system, and not have to rely so much on drugs, with their serious side effects.
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With love to all,
Joan Tendler
