For some people, coronavirus (COVID-19) can cause symptoms that last weeks or months after the infection has gone. There are two stages to what is commonly known as Long COVID:
It can affect multiple systems in whole body, and your symptoms can change and come and go over time. It has been seen that despite how severe or mild covid infection was, people still can develop prolonged symptoms. A wide range of long-term symptoms are reported, among others: chest pain, headache, muscle pain, pins and needles, forgetfulness, depression, loss of smell, persistent cough, shortness of breath, palpitations, diarrhoea, abdominal pain, rash, recurrent fever.
There are many reports from people who feel they do not regain their previous health following COVID-19. Preliminary results from a nationally representative sample survey by the UK Office for National Statistics estimates that around 1 in 10 respondents testing positive for COVID-19 may exhibit symptoms for a period of 12 weeks or longer. Other studies indicate that around a third of people testing positive for SARS-CoV-2 had not returned to their usual state of health when interviewed 3 to 6 weeks after diagnosis. In addition, recent studies found that 30% of COVID-19 patients surveyed still had persistent symptoms after nine months. It should be noted that the majority of patients surveyed (85%) were outpatients with mild illness. Some medical doctors have concluded that Long Covid develops due to not treated COVID-19 or not treated aggressively when this was needed.
Avoidance of exposure should be the number one strategy and has received the most attention. Methods of avoidance are described in the section below called Anti-Viral Hygiene. By avoiding infection, you help prevent spread to other people and benefit the entire community. Quarantines will delay the spread of infection and reduce the burden on the health care system, but they are not designed to eradicate the virus. Most people in the UK and U.S. are likely to be exposed to COVID-19 over the next year.
If you are exposed, there are measures you can take, based on the biology of the virus, which may diminish the likelihood of severe illness. These are not treatments for disease; they are preventive strategies to help place you among the 80% with mild to minimal illness and they have the greatest chance of succeeding if they are implemented before you are exposed. If it becomes possible to expand the 80% with trivial illness from COVID-19 to 90%, the social benefit will be enormous.
In order to cause disease, any virus must enter a human cell, replicate, and damage the cell, escaping to infect adjacent cells. For COVID-19, there are 3 enzymes that play a critical role in this sequence. They are named ACE-2, Furin and 3-CL protease.
ACE-2: COVID-19 enters human cells by attaching to a protein on the cell surface called ACE-2. The pattern of COVID-19 pneumonia on CT scan matches the distribution of ACE-2 in the lungs. ACE-2 is actually an enzyme with strong beneficial effects in the organs that produce it. When corona virus binds to ACE-2, the protein loses its enzyme activity. In the words of one scientist, COVID-19 produces “ACE-2 exhaustion”. Some scientists believe that ACE-2 exhaustion is responsible for the severity of pneumonia and for catastrophic effects like heart failure, blood clots and circulatory collapse. We believe that all the clinical manifestations of COVID-19 can be traced to ACE-2 destruction by the virus.
Laboratory studies have shown that restoring ACE-2 dramatically reduces the severity of pneumonia in animals with many types of lung injury, infectious or toxic, including those infected with SARS CoV-1, a close relative of SARS-CoV-2. The resilience of ACE-2 may explain the diversity of responses to corona virus infection. ACE-2 activity is highest in young animals and decreases with age. Conditions associated with death from COVID-19 infection (advanced age, diabetes, high blood pressure, heart disease, kidney disease) are all associated with diminished baseline ACE-2 activity. Because the gene for ACE-2 is located on the X-chromosome, women may have more ACE-2 than men. The second phase of COVID-19, the progression from a minor viral illness to severe pneumonia, may reflect ACE-2 exhaustion, occurring several days after the initial symptoms.
This protocol for protection will present aids to enhancing ACE-2 resilience. In order for the COVID-19 virus to lock on ACE-2, the surface of the virus (the viral spike proteins) must first be altered by an enzyme called Furin. Furin is present in all human cells; unlike ACE-2, it is not indispensible. Furin plays a role in the spread of cancer and various infections and there are drugs designed to block Furin. Some dietary components and herbal compounds have been shown to inhibit Furin activity.
A recent detailed analysis of the evolution of this virus through genetic analysis suggests the following conclusion: COVID-19 has been around for a long time as a source of occasional illness in humans. A series of mutations increased its sensitivity to Furin, allowing the virus to bind much more tightly with ACE-2, making it far more contagious and virulent, and creating the present pandemic. This research makes Furin an attractive target for slowing the spread of infection.
3 CL-PROTEASE: Once they have entered human cells, corona viruses produce damage and spread to other cells by creating an enzyme called 3CL protease. Although several enzymes may be involved in viral replication and spread, 3CL protease is the most important for the corona virus family. It has been called “the Achilles heel” of corona virus and is the subject of new anti-viral drug development. Some dietary flavonoids inhibit 3CL protease in laboratory studies and for that reason may limit severity of infection.
IMMUNE BALANCE: In order to accomplish the steps just described, viruses need to avoid the natural, intrinsic protection provided by the human innate immune system, a series of cells and proteins that kill viruses on contact. Corona viruses have many mechanisms for evading the innate immune system, so it isn’t clear that stimulating innate immunity will offer much protection. Weakened innate immunity may increase susceptibility to illness, so measures to optimize innate immunity are warranted. Once pneumonia develops and disease severity increases, the role of the immune system changes. Much of the damage is due to over activity of immune responses, which is termed a “cytokine storm.” Immune modulating therapies need careful handling during Phase Two of COVID-19 infection.
A few dietary components have shown anti-corona virus effects in laboratory studies, including results in animals. Some of these have a long history of human use for treating infections.
ACE-2 enhancement
Regular aerobic exercise and a plant-based whole foods diet are associated with improved ACE-2 function. Natural substances shown to enhance ACE-2 function include curcumin (a set of flavonoids found in the spice turmeric), resveratrol (a polyphenol found in red grapes and other foods), rosmarinic acid (a polyphenol found in spices like rosemary and oregano), Panax notoginseng (an herb used in some traditional Chinese medicines—the active Panax fractions for strengthening ACE-2 are called saponins), and alpha-lipoic acid (an anti-oxidant). ACE-2 as an enzyme produces a peptide called Ang 1-7, which is responsible for many of its cellular benefits. Ang 1-7 is made up of 7 amino acids and can be absorbed if taken orally. Availability of Ang 1-7 as a nutraceutical is desirable, but presently elusive.
Resveratrol has a number of beneficial effects on corona virus infection beyond ACE-2 support; it inhibits the growth of the deadly MERS corona virus by multiple mechanisms. In addition, resveratrol diminishes the kind of inflammation associated with corona virus infection.
Inhibition of Furin
Natural substances that inhibit Furin activity include the herb Andrographis paniculata, a staple of traditional Chinese medicine (the active fractions are called andrographolides), the flavonoid luteolin (found in celery, thyme, green peppers and chamomile tea), and an extract of noni leaf (Morinda citrifolia, the leaf not the fruit). In addition to inhibiting Furin, luteolin was shown to directly block the entry of SARS-Co-V-1 into cells by sticking to the surface spike protein
3CL protease inhibition
Elderberry fruit (Sambucus nigra) and the medicinal herb Houttuynia cordata both inhibit the viral enzyme 3-CL protease and have been shown to inhibit corona virus activity in cells. Elderberry seems to be most effective if started before infection occurs. It may be contra-indicated in Phase Two of COVID-19, because of its immune boosting effects. Elderberries’ 3CL protease inhibition is related to its content of flavonoids, especially those called anthocyanins, and its immune stimulating activity is related to its complex sugars (polysaccharides). If taking elderberry, make sure its flavonoid or anthocyanin content has been standardized. Elderberry extracts are safer than raw elderberry fruit. The leaves, bark and roots of elderberries contain a toxic substance, which is removed by cooking or extraction. Concerns have been raised about the immune stimulating effects of elderberries. These are addressed in the next section, because they apply to all immune enhancing therapies.
There are several dietary flavonoids that inhibit corona virus 3CL protease. The most studied are luteolin and quercetin, which is found in both elderberry and Houttuynia. Food sources of quercetin include onions, apples and many other fruits. Quercetin is presently being studied in China as a drug treatment for COVID-19, based on research initiated at McGill University. Other flavonoids with potent 3CL protease inhibition in laboratory studies include herbacetin, which is primarily found in ground flax seed (not in flax seed oil but in the husk) and theaflavin gallates, which are abundant in black and puerh tea. Green tea and oolong tea were inactive in this study. As long as you maintain hydration, black tea with elderberry concentrate may be the beverage of choice. Do not add milk to your tea, as milk interferes with theoflavin absorption.
There is a growing consensus that broad-based attempts to enhance immune function will not help and may hurt people suffering from COVID-19. Immune modulation for COVID-19 should vary with the stage of infection: pre-exposure/asymptomatic, Phase One/Phase Two. Some immune enhancers are sufficiently anti-inflammatory that they have a place in each stage; others should only be used for prevention or early asymptomatic infection.
For prevention, enhancement of innate immunity is reasonable, given the proclivity of this virus to sicken people who are older and therefore likely to have sub-optimal innate immune defenses. The innate immune system is present at birth and is ready to attack microbes on contact. Its function is supported by adequate sleep and moderate exercise. The most important dietary component for its maintenance is protein. Protein deficiency impairs innate immunity, but there is no evidence that excess dietary protein improves it beyond the effects of a normal healthy diet. Your protein intake in grams should be about half your lean body weight in pounds.
For symptomatic infection, anti-inflammatory approaches that prevent hyper-reactivity of the innate immune system are warranted. A key driver of the inflammatory damage in COVID-19 is a protein complex called the NLRP3 inflammasome. Quieting this complex should be a major treatment goal.
The safest substances are vitamin D, low dose melatonin, probiotics, prebiotics and mushrooms.
Vitamin D. Almost everyone should supplement with Vitamin D through the winter, but the dose needs to be individualized over a range of 1000 to 5000 IU/day. Vitamin D is best absorbed with a large meal. (A recent review cautioned about a possible pro-inflammatory effect of vitamin D. That report failed to recognize the different forms of vitamin D in the body. The common supplemental form of vitamin D is cholecalciferol, or vitamin D3. In the liver D3 is converted to 25-hydroxyvitamin D3, which is the main circulating form of vitamin D. At sites of inflammation and in the kidneys, 25-hydroxyvitamin D is converted to the most active form, calcitriol. Except in cases of severe deficiency, there is little relationship between vitamin D supplementation and levels of calcitriol. No observation that relates calcitriol level to inflammation has any impact on optimal vitamin D3 supplementation).
Melatonin is a hormone made by the pineal gland at the base of the brain. It supports anti-viral immunity and also helps to control NLRP3. Your body makes melatonin in the dark, mostly between 2-3 AM. Melatonin synthesis decreases with age, which may be one factor contributing to the impact of age on the outcome of COVID-19. Don’t watch late night television or use a video screen after midnight. Limit artificial lighting at night. Cherry juice contains low levels of melatonin (about 40 micrograms in 8 ounces). Drinking cherry juice (about 16 ounces a day) can significantly increase blood levels of melatonin. You can also take low dose melatonin as a supplement, about one half milligram (0.5 mg) around 10 PM. If you get sick, you may need more. At higher doses, melatonin inhibits the NLRP3 inflammasome. The anti-inflammatory effect of melatonin may be enhanced by high doses of vitamin C.
Medicinal and dietary mushrooms contain polysaccharides that can stimulate innate anti-viral immunity. The best to take in anticipation of SARS-CoV-2 exposure are turkey tail (Coriolus or Trametes versicolor) and reishi (Ganoderma lucidum). In addition to enhancing innate immunity, they can stimulate release of immune balancing, anti-inflammatory cytokines.
Probiotics and prebiotics may impact innate immunity by creating a gut microbiome that stimulates the immune system. Research in this area is in its infancy. Prebiotics with the best evidence for immune stimulation include beta-glucans, arabinogalactans and galacto-oligosaccharides. These are readily available as powders. Probiotics with the best evidence for immune stimulation are Lactobacillus species, especially Lactobacillus plantarum, which is found in sauerkraut and other fermented plant foods, and spore-forming bacteria of the genus Bacillus, which are normally found in soil. Several preparations are commercially available. Because COVID-19 has many mechanisms for evading innate immunity, even when it is strong, immune enhancement by itself is not a promising approach for preventing severe infection.
Elderberry polysaccharides have been shown to enhance innate immunity and prevent viral infections in air travelers. To be rich in polysaccharides, the elderberry extract must be produced by ultra filtration, not by solvent extraction.
Several physicians advise that zinc and vitamin A should be taken to prevent or treat COVID-19. Our view is that vitamin A and zinc should only be supplemented if blood levels are low, because of the potential toxicity of high levels of these nutrients. Vitamin A may cause liver toxicity. Zinc is much more complex. Zinc has been advocated at doses of 30 to 75 milligrams per day for its alleged direct anti-vital effects and for its inhibition of certain enzymes involved in viral transport and replication. This advice ignores the physiology of zinc. Levels of zinc in plasma, even when they are low, are about 10 times greater than those needed for inhibition of viral enzymes. The concentration of zinc inside cells is over 200 times higher than needed. Almost all the zinc within cells is bound to proteins, so that the concentration of free zinc is negligible, almost a million times lower than what is needed to inhibit viral-associated enzymes. There is no way that zinc supplementation will impact the level of free intracellular zinc. But high dose zinc supplementation will produce deficiency of copper, and copper is a natural inhibitor of Furin. Many integrative physicians make the mistake of measuring zinc in red blood cells or whole blood to establish zinc status; this is inaccurate, because intracellular zinc reflects the levels of zinc-containing proteins, which is not a guide to zinc deficiency or adequacy. Plasma zinc is much more meaningful. Inflammation leads to a sequestration of zinc in the liver, however, so in severe inflammatory states, plasma zinc also becomes an unreliable index of zinc status. Finally, dietary zinc supplementation increases the risk of bowel inflammation due to overgrowth of the pathogenic bacteria, Clostridum difficile. Dietary zinc increases toxin-production and virulence of C. difficile in laboratory animals and in humans. Hospitalization, especially when associated with the use of antibiotics or acid-suppressing drugs, is a major risk factor for C. difficile colitis. Zinc supplementation should not be used freely, but with caution.
The lung damage of advanced corona virus pneumonia is due to an overactive immune response, so some immune boosting therapies should be used only for prevention or early infection and not for severe illness. Fortunately, many of the substances already mentioned decrease inflammation and specifically down-regulate the NLRP3 inflammasome: resveratrol, luteolin, curcumin, andrographolides, and melatonin. There are many other dietary components that modulate NLRP3. Among these, black cumin seed (Nigella sativa and Nigella indica) has the most robust history of medicinal and clinical use. Their active ingredient is thymoquinone. Look for a product that specifies thymoquinone content (desirable is 5%).
If you suffer from an autoimmune disease, it may not be advisable to use melatonin, mushrooms, elderberry, prebiotics or probiotics that stimulate innate immune function. If you become sick with symptoms of COVID-19, you should stop the use of medicinal mushrooms elderberry and immune-enhancing pre- or probiotics.
Ever since the SARS-CoV-1 epidemic, which lasted from 2002 to 2004, scientists have been searching for drugs (old and new) to improve the outcome of corona virus infection. There are two categories of established, readily available, FDA-approved drugs that are promising.
2. Antihypertensives, a class called ARBs (angiotensin receptor blockers), which are normally used to reduce blood pressure and protect kidney function. ARBs increase ACE-2 activity and have been proposed as a treatment to promote healing of the lung in corona virus pneumonia. A recent study from China demonstrated through indirect measures that ACE-2 function declines with viral load and severity of COVID-19 pneumonia. For people already taking blood pressure medication, the inclusion of an ARB may improve the response to COVID-19 infection. The Federal government is sponsoring a trial of the ARB losartan for Amelioration of COVID-19. However, the ARB that most enhances ACE-2 levels in humans is Olmesartan (Benicar). Of all the ARBs, Olmesartan has the greatest impact on immune function. One caveat: a rare but serious autoimmune complication of Olmesartan has been described by the Mayo, severe diarrhoea mimicking celiac disease and/or lymphocytic colitis.
There is misinformation circulating on the Internet that attributes a high death rate with COVID-19 to ARBs and another class of drugs called ACE inhibitors. This opinion is speculative and based on no evidence; it reflects a faulty understanding of corona virus biology and the role of ACE-2 exhaustion in determining disease outcome. A recent study from China found no association between the use of ACE inhibitors or ARBs and severity of COVID-19.
SELECTED REFERENCES FOR HEALTH PROFESSIONALS (more will follow)
http://www.mcgilltribune.com/sci-tech/montreal-researchers-propose-a-treatment-for-covid-19-170320/ https://www.biolifesas.org/biolife/2020/02/04/mast-cells-contribute-to-coronavirus-induced-inflammation-new-anti-inflammatory-strategy/ https://www.ncbi.nlm.nih.gov/pubmed/15223557 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114094/
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