August 15, 2020
The Covid-19 pandemic has brought the world to a standstill for 3 reasons:
- It is highly contagious, spreading readily within groups of people .
- It is often spread by people who are asymptomatic . In fact, the virus appears to be most contagious before or soon after onset of symptoms .
- Although 80% of infected people have no symptoms at all or experience a trivial illness, about 5% develop a catastrophic disease requiring hospitalization and intensive care, which is associated with severe complications. In the New York metro area, during the first 5 weeks of the pandemic, the mortality rate for hospitalized patients in the Northwell Health system was 21%; 12% received invasive mechanical ventilation, and 3% required kidney transplantation . These rates may be changing (discussed below in RATES), but Covid-19 will definitely be the third leading cause of death in the U.S. in 2020, and possibly in 2021.
Unusual and mysterious manifestations of Covid-19 are increasingly common. Many people who recover from the acute illness are left with symptoms that last for weeks or months and may fluctuate from day to day. Covid-19 is clearly not just a bad case of the flu. Heart failure, circulatory problems, blood clots, digestive disorders, neurological and psychiatric symptoms, and autoimmune diseases may complicate Covid-19.
I began posting this guide to Covid-19 at the end of February, to organize my research into the emerging science and to cut through the deluge of false information on the Internet and the misleading information being repeated in news cycles. I have updated it periodically, as new data and new perspectives emerged. My goal is to help you make informed decisions for protecting your health and the health of those you care about and to be able to critically evaluate breaking news.
Corona viruses are a family of viruses made from RNA instead of DNA. There are many species that produce respiratory and gastrointestinal illness in humans and animals. Four strains cause the common cold. The pandemic corona virus, technically called SARS-CoV-2, first identified in Wuhan, China, causes the disease named Covid-19. Under the electron microscope, the virus looks like a medieval weapon: a globe covered with spikes. The spikes are made of protein (the viral spike proteins) and they are essential for viral entry into your cells.
SARS-CoV-2 is almost identical to a corona virus that has inhabited bats for about 70 years, but had never been identified as a cause of disease in people. The closest human pathogen to SARS-CoV-2 is the corona virus that caused SARS (Severe Acute Respiratory Syndrome) in 2003. On an individual case basis, SARS was far more lethal than Covid-19, but it was also far less transmissible. Over a 2 year period, SARS sickened 8098 people worldwide and killed 774. After 8 months, Covid-19 is already a thousand times more deadly than SARS. The genetic mutations that distinguish SARS-CoV-2 and that enable its high reproductive rate in humans are discussed in the section below on CORONAVIRUS BIOLOGY.
SARS-CoV-2 is readily transmitted from person to person, usually in respiratory droplets. Large droplets produced by a cough or sneeze may travel as far as 27 feet, hurtling at a speed of up to 200 miles/hour and then coasting on turbulent airflow . Breathing, talking, shouting and singing encase the virus within very small droplets that stay airborne as aerosols for up to 14 minutes if the air is totally still , longer, if the air is moving. SARS-CoV-2 can be sustained in the air of a closed air conditioned bus for at least 30 minutes without losing infectivity .A study from Wuhan found aerosolized SARS-CoV-2 in medical staff areas and unventilated bathrooms . In the cold, stale air of a meat processing plant, the virus was able to infect people 26 feet away from its source .
The role of airborne aerosols in the spread of Covid-19 is still controversial. After reviewing detailed data from several well-studied clusters, I have concluded that airborne aerosols play a significant role in “super-spreader” events, in which multiple people get sick from the same exposure. In the absence of shelter in place restrictions, super-spreaders may account for the majority of cases . Physical distancing may not protect against aerosol spread, but masks can be very effective (more on masks in ANTI-VIRAL HYGIENE). Air conditioning can increase transmission by keeping the virus airborne longer through two mechanisms: (a) creating currents on which the droplets drift and (b) decreasing humidity, so that the droplets remain smaller and lighter . Respiratory droplets absorb moisture from humid air to become larger and heavier, precipitating on to surfaces more quickly.
SARS-CoV-2 is mostly but not exclusively spread indoors. Despite the ease with which it spreads in crowds, the rate of spread from one individual to the next is relatively low. A prospective study in China found that close contacts of an infected person had a 3.7% chance of acquiring infection. The risk was greatest (10.3%) for household contacts . These rates are much lower than those found in ships at sea (see RATES).
Unenclosed outdoor spaces allow dilution of viral particles, aided by wind. Summer sunlight inactivates 90 per cent of viral particles suspended in saliva within 7 minutes; on a dry surface it takes twice as long . Winter conditions double the time required. But clusters of cases related to backyard barbecues and other outdoor activities where people were in close contact have been described  and outdoor transmission has been documented in China, so Covid-19 can clearly be acquired outdoors.
THE KEY ROLE OF THE NOSE
The principle site of entry of the virus is the lining of the nose. Here the virus replicates, increasing in number before aspiration into the lungs, where pneumonia occurs . Having multiplied in the nose, SARS-CoV-2 is in a strong position to invade both the brain and the blood vessels. The initial viral load seems to be a key factor determining the severity of infection, so that covering your nose with a mask – almost any mask – may protect you, in addition to preventing spread to others ) More on this in ANTI-VIRAL HYGIENE). The role of the nose as an incubator for Covid-19 suggests that an anti-viral nasal spray may help decrease transmission among individuals at high risk of exposure  (More about nasal sprays in OLD DRUGS REPURPOSED).
Airborne virus will settle on solid surfaces and air vents and remain viable on these surfaces for varying periods of time . This does not appear to be a major route of transmission, however. Passengers traveling by rail in China who occupied a seat that had just been vacated by a person with Covid-19 were no more likely to get sick than people in other parts of the train who had no contact with the infected person . The major determinants of risk on trains were proximity to the infected person and duration of travel together. Sitting next to a person with Covid-19 created a 3.5 per cent risk of infection that increased by 1.3 per cent for every hour of travel. (More about surface contamination in ANTI-VIRAL HYGIENE).
SARS-CoV-2 can attach to cells of the small and large intestines , appearing in bowel movements. Flushing a toilet with the lid open may then allow viral particles to become airborne. The virus frequently contaminates sewage. A small study demonstrated that when found in stool the virus is not only viable but infectious  For many people it persists in stool when respiratory swabs are negative . (For more on Covid-19 and the GI tract, see THE GUT MICROBIOME AND COVID-19). Food-borne or water-borne infection is possible but still unproven . During the outbreak on the Diamond Princess cruise ship, 15 of the first 20 people infected were food handlers, leading some researchers to believe that food-borne infection may have played an important role in that cluster . A report from China described a shipment of shrimp in which the packaging was contaminated with SARS-CoV-2 (the shrimp itself was not) . Another report found chicken wings to be contaminated with SARS-CoV-2 , but the infectivity of the virus on food has not been estabhlished..
STAGES OF INFECTION
The incubation period from exposure to illness is 2 to 14 days, with an average of 5 days. Unlike the flu, COVID-19 often starts gradually and the presenting symptoms are extremely variable. There may be no fever, even with severe illness. Common early symptoms include fatigue, aches and pains, headache, sore throat, dry cough, stuffed or runny nose, nausea and loss of appetite. For some people, the first symptom is abdominal pain without respiratory complaints.
LOSS OF SMELL EXPLAINED
Loss of smell and taste occurs frequently with Covid-19, often without nasal congestion. When not associated with a stuffed nose, loss of smell is caused by swelling of an area at the top of the nose called the olfactory cleft . Swelling is associated with viral invasion of a group of cells that surround and support the olfactory nerve, which carries the sense of smell to the brain . They’re called sustenacular cells. Swelling in this area can damage the olfactory nerve in 2 ways: (1) There may be inflammatory chemicals (cytokines) released by the sustenacular cells that spill over and damage the nerve. (2) Local swelling may put pressure on the nerve, creating what is called a pressure neuropathy. It usually clears within days to weeks. Pressure neuropathies can be helped by the antioxidant alpha-lipoic acid, 600 mg/day  (more on alpha-lipoic acid in ACE-2 ENHANCEMENT), possibly in combination with gamma-linolenic acid (GLA), found in evening primrose and borage seed oils .
Other early symptoms of Covid-19 can include diarrhea, skin rashes or skin mottling (mottling is an ominous sign that may precede blood clotting), a purple discoloration of the toes and (rarely) epileptic seizures. For 80% of people, the initial symptoms last about 5 days and are followed by recovery. I call this Phase One illness and for many people it is the only phase.
For 20%, there is a Phase Two with increasing cough, shortness of breath, fever, worsening fatigue, brain fog, dizziness and mood instability. Abnormal swings in heart rate and blood pressure when going from lying or sitting to standing may occur; these can explain the dizziness and fatigue. They may indicate dehydration and a need for more salt and water, or might indicate damage to the autonomic nervous system. When they occur, they should be followed closely; in my experience, the clearing of these swings is associated with recovery.
The speed and pattern of recovery from Phase Two illness is very variable. Between 10 and 50 per cent of people experience fluctuating post-infectious symptoms that can last for weeks. Microscopic clots in blood vessels are common with Phase Two illness; their presence is suggested by a blood test called D-dimer, which should be run on everyone who is sick with Covid-19 . An elevated D-dimer must be repeated and followed. It may portend a serious complication like pulmonary embolism or stroke and may require anticoagulation. Many people with Phase Two illness show a reduction in oxygen levels in blood. Having an inexpensive fingertip pulse oximeter at home is a way to measure oxygen levels if you are sick. A normal reading is 95 to 99; anything less than 93 requires emergency evaluation.
A small percent of people with Phase Two illness become sick enough to require hospitalization. I call this Phase Three. Almost all the clinical research on Covid-19 has been done with people suffering from Phase Three illness. The major indicators for hospitalization are low blood oxygen levels, complications of blood clots like strokes and pulmonary embolism, severe neurological or cardiac problems, kidney failure and bone marrow suppression. A low lymphocyte count is predictive of poor outcome . Lymphocytes are one of the two major classes of white blood cells, routinely measured whenever a CBC (complete blood count) is ordered. (More about lymphocytes in the section on IMMUNITY).
The treatment of Covid-19 in hospitals is outside the scope of this guidebook, except for one important observation: a precipitous drop in blood oxygen concentration may occur; much of the time this is not due to pneumonia but to poor circulation of blood flow within the lungs . This should not be treated with mechanical ventilation but by high dose oxygen and by measures that improve the regulation of blood flow . Understanding this fact saves lives.
As global experience with Covid-19 increases, it has become clear that many people who are sick, even those with minor illness, do not experience a smooth and rapid recovery. Symptoms like fatigue, fever, pain, breathing difficulties, brain fog, mood swings and circulatory problems may continue for weeks or months, fluctuating in intensity . In a small study from Rome, 90 per cent of people hospitalized for Covid-19 continued to have symptoms of the disease 2 months after discharge.  A survey of Americans with relatively mild disease, found that 35% had not fully recovered 3 weeks after initial diagnosis. Fatigue, cough and headache were the most common symptoms; they persisted in one fifth of healthy young adults with no pre-existing medical disorders and in almost 50 per cent of those over the age of 50 . This is Phase Four, and it is the least studied phase of all. People who have recovered from Covid-19 show distinctive abnormalities of immune function that can predispose to ongoing inflammation .
Whether sick or well, infected people may shed the virus in secretions for more than two weeks . There are individual reports of prolonged viral shedding (up to 60 days), but it it isn’t clear how long these people are actually contagious.
Three important questions about immunity impact prevention and treatment of Covid-19:
- What aspects of the immune system can prevent serious infection?
- How does the immune response affect people who are sick?
- After recovery, are you immune from repeat infection?
The answers to each of these are complex and subject to change. Although it makes sense that a “weakened’ immune system should increase susceptibility to the virus, that fact has never been proven. In contrast, one report indicates that people receiving immune suppressive drugs for organ transplantation are not at increased risk of severe infection .
What is certain is that most people who enter Phase 3 of Covid-19 have a hyperactive immune response (a “cytokine storm”), which plays a major role in increasing severity of illness. To understand this paradox, you need to first recognize that the immune system is like an orchestra, not like a radio. There is no single volume control (softer vs. louder, weaker vs. stronger).
A QUICK OVERVIEW OF IMMUNE FUNCTION
Optimal immune function depends on the balance and coordinated flow of every part of the immune system as it relates to every other part. Like an orchestra, the immune system contains distinct sections or divisions.
The first division separates the innate and the adaptive components of the immune system. As its name implies, the innate immune system is present at birth. Its activity depends upon the interaction of various proteins in blood and certain types of white blood cells. Its chief characteristic is that it lacks a memory. It is programmed to automatically respond to certain molecular motifs that indicate foreign invasion or tissue damage.
The adaptive immune system, in contrast, must be educated. It learns to recognize specific proteins called antigens and acts to neutralize or destroy them. The adaptive immune system is divided into two major arms, called the cellular response and the antibody response, both carried out by lymphocytes.
Antibodies are proteins designed to attack specific antigens; they are made under the direction of B-lymphocytes (B-cells). The cellular immune response is driven by T-lymphocytes, of which there are many types: T-helper cells, T-suppressor cells, regulatory T-cells, killer T-cells, and sub-divisions of these classes.
Working together, T and B lymphocytes organize a coordinated immune response that attacks pathogens while limiting collateral damage.
ANTIBODIES IN COVID-19
Antibody responses have grabbed the most attention. Convalescent plasma, which is rich in antibodies to SARS-CoV-2, appears to speed recovery of critically ill patients.  Many people infected with SARS-CoV-2 do not develop antibodies, however , and among those who do, antibody levels may drop sharply after 20–30 days . Sicker people tend to have higher antibody levels than infected people who are not sick, which suggests that those who do not get sick manage to avoid illness through a mechanism other than production of specific antibodies.
T-LYMPHOCYTES AND COVID-19
The limited usefulness of antibody levels for diagnosis of Covid-19 and their lack of correlation with outcome is shifting attention to T-lymphocytes. Testing the activity of T-lymphocytes is very demanding, so large scale studies have not been done, but small studies have shown that people with Covid-19 may develop strong T-cell responses to the virus, even if they do not make measurable antibodies to SARS-CoV-2 . As opposed to antibody responses, a strong T-cell response is associated with milder disease. Increasing severity of illness is associated with loss of T-lymphocytes. A decline in total lymphocyte number on a routine blood count is one sign of this.  Loss of the restraining influence of T-cells may contribute to the cytokine storm of critical illness.
DO COLDS PROTECT YOU FROM COVID-19?
Intriguing research on T-cells has been receiving a lot of attention recently, and, as usual, has led to unsubstantiated speculation. Apparently, people who have never been exposed to Covid-19, including people whose blood cells were stored and frozen between 2015 and 2018, often show T-cell reactivity to SARS-CoV-2 . The researchers attribute this to cross-over reactivity among people who have had previous exposure to other corona viruses, such as the four strains that cause the common cold. They speculate that this T-cell responsiveness may help protect people from infection and account for the large number of people who get no symptoms when infected with SARS-CoV-2.
I find some flaws in their logic, because there are critical questions that remain unanswered: What is the corona virus T-cell reactivity of people who get frequent colds, or who have had a recent cold? Are people with recent colds more or less likely to contract Covid-19? Are people with frequent colds more or less likely to contract Covid-19? The last two questions can be easily answered with surveys. Until those questions are answered, I don’t believe that any conclusions can be drawn about the potential benefit (or harm) of pre-existing T-cell reactivity to SARS-CoV-2.
THE INNATE IMMUNE SYSTEM AND COVID-19
The innate immune system plays a dual role in Covid-19, which is complicated by the ability of the virus to evade attack by innate immunity, even when it is robust .
Some components of the innate immune system are able to prevent infection or reduce severity of disease . SARS-CoV-2 is readily inactivated by proteins called Type 1 Interferons, which are produced by cells of the innate immune system . Interferons also up-regulate production of ACE-2 in the lungs, which can have a protective, anti-inflammatory effect in the face of corona virus infection .
SARS-Co-V2, however, is uniquely able to fool its human host into producing very little Type 1 Interferon, so even someone with a strong innate immune response lacks this first line antiviral defense , leaving other components of the innate immune system to increase inflammation and tissue damage .
Two cell types of the innate immune system are related to increased severity of Covid-19: neutrophils and mast cells. The ratio of neutrophils to lymphocytes increases with disease severity.  Mast cells are the main source of cytokines in the lungs . A role for mast cells in Covid-19 is suggested by a study from the University of Virginia. Among people hospitalized with Covid-19, a higher blood level of a cytokine called Interleukin-13 (IL-13) predicted increased likelihood that mechanical ventilation would be needed . IL-13 is produced by mast cells and has distinctive effects in the body (more about its role in the sections on CORONA VIRUS BIOLOGY and MAST CELL ACTIVATION).
The bottom line: attempts to “strengthen” the immune system by broadly boosting innate immunity may help other viral infections but can backfire when applied to Covid-19. The approach most needed is one that helps your cells overcome the evasive tactics that blunt the initial Type 1 Interferon response. (More about this in TRAINED IMMUNITY, AN EMERGING CONCEPT).
RATES (for people who think this pandemic is overblown)
There is so much controversy around the statistics related to Covid-19, especially mortality rates. The most fundamental fact is that rates of infection, complications and mortality vary with the group being studied. The risk of infection is related to level of exposure, not to age or underlying health status. The risk of severe illness increases with advancing age, and with the presence of high blood pressure, obesity, diabetes, and heart or kidney disease. About 40% of U.S. adults suffer from one of these underlying conditions .
The clearest data for mortality among ambulatory, well-fed individuals comes from epidemics at sea, in which everyone onboard was tested. The Diamond Princess cruise ship had a population that was mostly middle-aged and elderly. The rate of infection was about 20% and the infection fatality rate was 1.4%. (For every 1000 people infected, 14 people died). This is 5-10 times greater than the mortality rate for seasonal flu among a comparable population. All the deaths occurred in passengers above the age of 70, but younger passengers were more likely to have symptoms of infection than older passengers.
The crew of the USS Theodor Roosevelt was mostly healthy young seamen. Although the rate of infection was the same as on the cruise ship (about 20%), the apparent infection fatality rate on the naval vessel was only 0.1%. This low rate is nonetheless about 5 times as high as the fatality rate among men of the same age afflicted with seasonal flu .
An outbreak of Covid-19 interrupted a cruise to Antarctica during March, 2020. Although the crew and passengers were carefully screened for risk of infection before departure, one person developed a fever on day 8 and all 217 people on board were then tested and followed.  Of these, 59 per cent tested positive for COVID-19 on nasal swab, but only 19 per cent of those infected had any symptoms. Among the people who became ill, 8 people (6.2 per cent) required medical evacuation, 4 people (3.1 percent) required mechanical ventilation and 1 died, an infection fatality rate of 0.8%. These are the statistics for Covid-19 among a group of people well enough to fly to Argentina and undertake adventure travel in a relatively small ship.
In the Skagit County choir (almost all women), one person spread SARS-CoV-2 to 52 of 61 people (attack rate of 86%) and 2 people died (infection fatality rate of 3.2%). These high numbers are almost certainly due to the high viral load generated by a person with Phase One illness singing in a closed space with others for over 2 hours.  Among workers in U.S. meat packing plants, there were about 5000 cases of Covid-19 reported in 19 states by May 1, with 20 deaths , a case fatality rate of 0.4%. Systematic screening of 1800 residents of Miami-Dade County in late April found that 6% of people had been infected with SARS-CoV-2 . If that number is applied to the entire county, the infection fatality rate there would have been about 0.3%. The huge increase of cases in late spring overwhelmed testing facilities, so the present infection fatality rate is unknown.
In the middle of June, the daily number of reported new cases of Covid-19 in the U.S. began a steady, dramatic increase. By mid-July, as would be expected, the daily toll of death also began to increase, although the case fatality rate has been quite a bit lower than it was during March and April. There are 3 possible explanations for this: (1) Covid-19 is infecting a younger group of people, as the older and more vulnerable continue to isolate themselves. Younger people have a better prognosis. (2) Doctors have more experience with this disease now and are more likely to introduce measures like anti-coagulation at an early stage, averting some of the complications. (3) Population-wide vitamin D levels are higher during the summer; the mortality rate of patients hospitalized with Covid-19 is inversely proportional to the blood level of vitamin D . (More about vitamin D below, under ACE-2 ENHANCEMENT).
The bottom line: there is marked variability in infection fatality rates, which is the percentage of infected people, including those without symptoms, who will die from Covid-19, and also in case fatality rates, which is the percentage of symptomatic people who will die of infection.
These rates have major implications for the scope of the pandemic in the U.S. and its consequences. First – and most important – everywhere it is studied Covid-19 is several times more deadly than the flu. Second, the actual number of cases that have occurred in the U.S. must be at least 10 times higher than the number of confirmed cases. At any given moment, there are hundreds of thousands of asymptomatic Americans carrying live virus that is readily transmitted to other people. These numbers also imply the cost of natural “herd immunity”, assuming that is even possible to achieve. With an infection fatality rate of 0.4%, by the time 70% of the U.S. population has been infected, one million people will have died from Covid-19.
[Note: a comprehensive set of references for the remainder of this document will follow. Compiling them and placing them in the document is very time consuming.]
The only way we will overcome the pandemic is by understanding the complex biology of SARS-CoV-2. I have relied on this biology in crafting treatment and prevention recommendations for my patients.
In order to cause disease, any virus must enter a human cell, replicate, and damage the cell, escaping to infect adjacent cells. Most anti-viral drug development attempts to block viral replication. But cell entry and cell damage can be prevented with strategies that are readily available now.
PART 1. Viral Entry, the Front Four
The entry of SARS-CoV-2 into human cells is a multistep process, in which every part is essential. Addressing each of these steps is the core of an integrated management approach to stopping Covid-19 at the cellular level.
There are four human molecules that enable SARS-CoV-2 to enter your cells. I call them the Front Four because cellular entry is the gateway through which infection occurs. They are all found in or on the cell membrane. Their names are heparin, furin, ACE-2, and TMPRSS2. Treatments that target each of these already exist and may prevent or limit viral entry and the damage it creates. They have been largely ignored in the trillion dollar race to develop antiviral drugs and vaccines.
- Heparin is a complex sugar that coats the outside of all human cells. Purified heparin is used in medicine as an anticoagulant drug, given by injection. The viral spike protein of SARS-CoV-2 sticks to heparin on the cell membrane, kind of like Super Glue . Heparin holds the virus in place  so that the next substance, furin, can do its job.
- The good news: purified free heparin, an FDA-approved medication, binds to the viral spike protein as readily as membrane-bound natural heparin. It can act as a decoy, filling up all of the virus’s heparin binding sites, so that the virus cannot stick to your cells .
- Researchers have proposed administering heparin through a nebulizer, inhaled into the lungs, to limit viral spread in people who are sick .
- Because the main port of entry for SARS-CoV-2 is the nose, I created a simple formula for a heparin nasal mist, with the goal of preventing viral attachment to cells lining the nose at the time of exposure. The product can be made in a medical office or a compounding pharmacy at minimal cost. Directions are available from my office for any physician or pharmacist who is interested, and I can prescribe this for my patients. (More on heparin in the section called OLD DRUGS REPURPOSED).
- Furin, like heparin, coats all human cells , but it’s an enzyme, not a sticky sugar. Its role in Covid-19 is to split the viral spike protein in two, so that it fits tightly into its cellular receptor, ACE-2, the way a key fits into a lock . Without priming by furin, the viral spike protein does not attach to the cellular receptor and the virus cannot enter a cell. The place on the viral spike protein that sticks to heparin (the heparin binding site) overlaps the place where it’s split by furin (the furin cleavage site). This relationship has enabled the pandemic.Genetic studies of the evolution of SARS-CoV-2 find that the predominant mutations separating SARS-CoV-2 from its relatives involve the furin cleavage site. They make the viral spike protein more susceptible to being cut by furin. Changes to the furin cleavage site are also the dominant mutations in the virus’s evolution since it spread through the Americas, indicating that furin is critical for high transmissibility.
- The good news: Because furin plays a role in promoting cancer and certain well-known infectious diseases, like anthrax, there has been a lot interest in furin inhibitors . Two natural substances that inhibit furin are widely available:
- Andrographis paniculata, an herb used in traditional Chinese medicine. (The active ingredients are called andrographolides)
- Luteolin, a bioflavonid found in celery, thyme, green peppers and chamomile tea, among other food sources.
- Both Andrographis and luteolin have anti-inflammatory effects that are separate from furin inhibition and which have been demonstrated in human clinical trials. Luteolin is also a natural inhibitor of IL-13, the cytokine found to predict a need for mechanical ventilation in hospitalized patients, and of mast cells, which contribute to the cytokine storm of critically ill patients. (More in the section on MAST CELL ACTIVATION).
- ACE-2, a protein embedded in the human cell membrane,is the centerpiece for viral entry, so it’s called the cellular receptor. Unlike furin or heparin, ACE-2 is only found in certain types of cells, where it bridges the entire thickness of the membrane, from outside to inside. SARS-CoV-2 can only enter cells that express ACE-2 in their membranes. This discovery has created a great deal of confusion about the role of ACE-2 in Covid-19. During the first few months of the pandemic, ACE-2 achieved undeserved notoriety as the villain that allows the virus to make us sick. Some researchers argued that people became sick because they had an excess of ACE-2 in their cells. This idea has been proved totally wrong, but it continues to pop up in news articles and some research papers, because it seems so simple. It’s based on a superficial understanding of the complexity of ACE-2 and its multifaceted role in maintaining physiologic balance.ACE-2 is an enzyme that is vitally important for your health. It protects your blood vessels, your heart, your brain, your lungs, your kidneys and your bone marrow from many types of damage, inhibits inflammation, prevents abnormal blood clotting and enables healing without scarring. When a corona virus binds to ACE-2, the protein loses its enzyme activity. ACE-2 is the victim not the cause of Covid-19 and loss of ACE-2 underlies all the terrible complications of Covid-19, including pneumonia, heart failure, blood clots, kidney failure, strokes, seizures, brain fog, purple toes, loss of lymphocytes, excessive inflammation and autoimmune disease.Support for ACE-2 and its functions is critical for reducing severity of Covid-19. Ideally, ACE-2 support starts long before exposure to the virus. The details are described in the section called ACE-2 ENHANCEMENT.
- TMPRSS2, like ACE-2, is an enzyme imbedded in human cell membranes. Like ACE-2, it is only found in certain types of cells. As the viral spike protein locks into ACE-2, TMPRSS2 cuts a wedge out of both, destroying the beneficial activity of ACE-2 and freeing the virus to pass through the cell membrane. The only cells that the virus can enter are those few cell types that express both ACE-2 and TMPRSS2 in their membranes. The highest co-concentration of these two enzymes demonstrated so far occurs in the cells that line the nose. Co-expression is also found in the lungs, the salivary glands, the heart, the small and large intestines…and…In these cells, it appears that the rate-limiting step for viral entry is the level of TMPRSS2, not the level of ACE-2. Inhibition of TMPRSS2 reduces viral entry by about 90%.Expression of TMPRSS2 in the cells that carry it is quite variable. Two factors that increase its expression are male hormones (androgens) and the cytokine IL-13, which is associated with increased severity of illness in hospitalized patients. Interleukin 13, in fact, increases TMPRSS2 and decreases ACE2, a combination of effects that is likely to increase severity of Covid-19 .
- The good news: Inhibitors of TMPRSS2 exist, although none are readily available in the U.S. The strongest and safest of these is a cough medicine called bromhexine, which has been used in Europe, Asia and Latin America for decades. (More about bromhexine in OLD DRUGS REPURPOSED).
- Researchers are looking at anti-androgen therapy for relieving severity of Covid-19. Two herbal extracts shown to decrease TMPRSS2 expression by inhibiting its activation through androgen signaling are baicalein (from the Chinese herb, Scutellaria baicalensis) and glycyrrhizin, the most active component of Chinese licorice. Both have additional anti-inflammatory and anti-viral effects.
- There are several natural inhibitors of IL-13. IL-13 plays an important role in asthma and allergies. It is secreted by several types of cells, including lymphocytes and mast cells. The high level of IL-13 in seriously ill patients with Covid-19 may be the result of the disease, but may also contribute to a heavy viral load by increasing levels of TMPRSS2. Foremost among these IL-13 inhibitors is the flavonoid luteolin, which we already met as an inhibitor of furin, and black cumin seed oil, an ancient health food used for medicinal and culinary purposes throughout the Middle East. The active ingredient in black cumin seed is thymoquinone, which has demonstrated anti-inflammatory, anti-viral and anti-toxic properties and has a long history of safe human use. Both luteolin and black cumin seed oil have been proposed as treatments that might mitigate the symptoms of Covid-19. (More on luteolin and thymoquinone in the section on MAST CELL ACTIVATION).
The bottom line: Prevention of viral entry and protection of ACE-2 are rational and actionable approaches to thwarting Covid-19 that can be implemented now.
PART 2. After Entry : the Role of NSP’s (non structural proteins)
Once inside your cells, the corona virus takes over the normal cellular machinery to replicate itself. It re-creates its structural proteins, like the viral spike protein. It also produces novel non-structural proteins (nsp’s) to evade your immune system, punch holes in your cells and reproduce itself. Most new drug development involves attempts to inactivate the nsp’s that contribute to Covid-19. If you follow the news feeds, you’ll be reading a lot more about nsp’s in the months ahead. One of them, nsp-5, also known as the main protease or 3CL-protease, is very important for viral spreading. It’s been called the “Achilles heel” of the corona virus family. In the laboratory, inhibition of 3CL-protease can totally block replication of SARS-CoV-2. Natural inhibitors are already known. They include:
- Polyphenols found in food. The polyphenols most likely to inhibit 3CL-protease are the flavonoids, because of their chemical structure. The most studied are luteolin and quercetin. You’ve already met the versatile luteolin. 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. Do not add milk to your tea, as milk interferes with theoflavin absorption.
- Baicalein from Scutellaria baicalensis….
- Elderberry fruit (Sambucus nigra), which is a potent inhibitor of 3-CL protease in test tubes and 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. Elderberry can increase production of a pro-inflammatory cytokine called TNF-alpha, which plays a major role in the cytokine storm of Covid-19. I recommend that elderberry be used primarily to prevent illness and that it should be stopped if symptoms occur.
- Houttuynia cordataan herb that is widely used in traditional Chinese medicine. In addition to anti-microbial effects, it has also been shown to inhibit inflammation. It has generally served my symptomatic patients well.
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, a close relative of SARS-CoV-2. Administering ACE-2 intravenously or through ACE-2 secreting stem cells has been proposed as a treatment for people who are critically ill with Covid-19. The second phase of COVID-19, the progression from a minor viral illness to severe pneumonia, blood clotting and circulatory problems, may reflect ACE-2 exhaustion, occurring several days after the initial symptoms.
Many lifestyle factors influence ACE-2 activity in your body. Regular aerobic activity is good; high intensity interval training is even better. A whole foods diet rich in plant-based polyphenols is good. Herbs and spices like spearmint, sage, thyme, rosemary and oregano contain the polyphenol rosmarinic acid, which supports ACE-2 activity. High concentrations of fructose are bad. Avoid anything made with high fructose corn syrup; the fruit you eat should be flavonoid rich, like berries. (More about diet in the section called INSULIN, LEPTIN AND COVID-19).
Vitamin D is essential for normal ACE-2 function. Vitamin D deficiency impairs ACE-2 and should be prevented by exposure to sunlight or by supplementation. During winter, the sun is not strong enough throughout most of the U.S. and supplementation is needed. The dose needed will vary from person to person and may be as high as 6,000 IU of vitamin D3 per day. Vitamin D is best absorbed with your main meal. The mortality rate of people hospitalized with covid-19 is inversely proportional to vitamin D level in blood. The higher the level, the less likelihood of dying.
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), 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).
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.
Estrogen also increases ACE-2 activity, which may be one reason that the prognosis of COVID-19 is better for women than for men. Testosterone, on the other hand, increases activity of TMPRSS2, an enzyme that destroys ACE-2 activity when corona virus enters your cells.
I began advocating ACE-2 enhancement for protection against Covid-19 in early March, as soon as it became clear that ACE-2 is the cellular receptor for SARS-CoV-2. Confusion around the role of ACE-2 in Covid-19 created some confusion around my recommendations. The section below was written to eliminate the confusion. It’s technical. You don’t need to read it to understand the program, but it will help you cut through the misinformation that continues to seep into news media and press releases.
A QUICK DEEP DIVE WITH ACE-2
The most basic principle in biology is the balance of opposites: everything that happens triggers its opposite. Every stress response stimulates an anti-stress response. The road to inflammation creates a road back from inflammation. ACE-2 is part of that counter response. When the level of ACE-2 in cells goes up or the genes creating ACE-2 become more active, ACE-2 is responding to a stressor as part of the body’s healing response.
The benefits of ACE-2 do not necessarily occur in the cells where ACE-2 is made. The benefits occur when the cells that produce ACE-2 release it into the circulation. Circulating in blood, ACE-2 is an enzyme that destroys two chemicals that play major roles in increasing severity of Covid-19: angiotensin-2 and desarg-9-bradykinin . The names are not important. What is important is that people who are critically ill with Covid-19 have highly elevated levels of these factors in their blood and in their lungs, because they have lost ACE-2 activity. When researchers state that ACE-2 levels are higher in certain states that increase the risk of Covid-19, they are missing the point. Elevated ACE-2 is not the cause of the risk, but the body’s attempt to compensate for that risk.
In addition to breaking down substances that cause inflammation, blood clots, brain injury and circulatory problems, ACE-2 also produces a substance that on its own improves circulation, turns off inflammation, prevents blood clots, enhances healing, and protects the brain and the bone marrow. That substance is called angiotensin 1-7 (Ang 1-7). Scientists at the University of Arizona and University of Pennsylvania are conducting clinical trials of Ang 1-7 to treat or reverse complications of Covid-19 in hospitalized patients. I am working with a compounding pharmacy to make an oral form of Ang 1-7 available to people with early disease, to prevent the need for hospitalization.
Let’s dive a little deeper. The cellular benefits of Ang 1-7 occur because Ang 1-7 activates a protein called the Mas Receptor. There are some substances that directly activate the Mas Receptor, by-passing ACE-2 and Ang 1-7. They are called “Mas Receptor agonists” (an agonist is the opposite of an antagonist) and they might compensate in part for loss of ACE-2. Two natural Mas Receptor agonists are widely used in traditional Chinese medicine: the herbs Scutellaria baicalensis (the active component is called baicalein) and Astragalus membranosus (the active components are called Astragalus root polysaccharides). Their potential use is described below in sections on INTEGRATED VIRAL MANAGEMENT and in POST-VIRAL FATIGUE SYNDROME.
A great deal has been written about balancing immune responses and controlling inflammation to treat Covid-19. Based on the known biology of SARS-CoV-2, I believe that the foundation for establishing immune balance and for control of inflammation is protecting and/or restoring ACE-2 and its normal physiologic function.
APPLYING INTEGRATED VIRAL MANAGEMENT
Know the rates of infection in your community. Are there clusters or hot spots? Know the habits and behaviors of people you engage with. Your circumstances should guide the steps you will take.
- If you have no symptoms, are you sheltered-in-place, exposed only to other people as careful as you are? Risk of exposure is minimal. Your main goal is promoting the resilience of ACE-2 and establishing a balanced immune response, because at some time you are likely to meet SARS-CoV-2.
- If you have no symptoms, but are possibly or probably exposed because your work or school or travel or social encounters bring you into contact with people whose habits and behaviors are unknown to you, you need to understand the principles described in ANTI-VIRAL HYGIENE. In addition to ACE-2 enhancement, you can take steps that would help to neutralize the virus at the time of exposure.
- If you have symptoms that might be caused by Covid-19, you must isolate yourself from other people whom you might infect and implement a treatment protocol to inactivate the virus and prevent complications. Medical treatment may be needed in addition to self-help measures. Anti-viral hygiene will help you keep others from getting your disease.
- If you are recovering from Covid-19, you need to understand that you may not have developed long-term immunity. If you still have symptoms, there are self-help treatments you can apply that may decrease the impact of the infection to restore your health.
The first step is to develop these habits: Wash your hands with soap and water for 20 seconds before eating, touching your face, after being with other people and when you return home. A face wash is also a good idea. Soap is the ideal anti-coronavirus cleanser, because it destroys the virus’s protective envelope. Do not use antibacterial soap; it will not kill viruses and will only damage your skin’s microbiome.
Use caution with objects or surfaces that are possibly contaminated; avoid touching doorknobs or elevator buttons with your hands. The following cleansers will kill most viruses, including corona viruses, on hard surfaces with 30 seconds of contact: 70% alcohol, 0.5 % hydrogen peroxide, 0.1 % bleach (hypochlorous acid). Note: The only alcohol you want to use is pure ethanol. Unfortunately, there has been a proliferation of products that contain methanol, a toxic relative of ethanol. The FDA maintains a growing list of these . You can search it at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-methanol#products
The FDA has recently cautioned against contamination of handsanitizers with 1-propanol, which may cause sedation .
Studies of the anti-viral effects of cleansers have been done on hard nonporous surfaces, so alcohol, peroxide or bleach will work on counter tops but may not work the same on your skin or other porous surfaces. If you choose to use bleach, make sure you do not mix it with ammonia, because the combination produces a deadly gas. Purelle hand sanitizer is 70% ethanol and might be an adequate substitute for soap, if you can find it, but remember that contact needs to be maintained for 30 seconds. Clean door knobs, phones and keyboards daily or more often.
If you have concerns about the safety of letters or packages you receive, remember that direct sunlight inactivates 90 per cent of SARS-CoV-2 in 15 to 30 minutes on a dry surface, that the virus survives on cardboard or untreated paper for only 24 hours and on plastic or steel for about 72 hours. If you have the option, you can leave a carton in your garage or on your porch until it is likely to be free of live virus. If the contents have been packed more than 3 days before you open it, there should be no infective viral particles contained within.
As for food, cooking kills the virus and microwave ovens can kill some strains of corona virus within 20 seconds at high heat. For helpful information about handling food safely, view this YouTube video: https://youtu.be/sjDuwc9KBps.
Ultraviolet light (UV-C, antimicrobial spectrum) kills most viruses, including SARS-CoV-2, although it may take 30 minutes of exposure to do the job. Portable home units are available. They must be used in a room or space where neither your skin nor eyes experience more than transient exposure, because prolonged or repeated exposure can damage eyes and skin.
The use of face masks has become a major strategy in the fight against Covid-19 and numerous studies have shown that when the majority of people routinely wear facial covering outside their home, the rate of transmission is significantly reduced. A great deal of new information about masks has been amassed, based on research that tries to answer these questions: What type of mask is best? How effective is each kind? Is there a downside? Here are some important pointers:
- To offer any benefit, a mask must fit snugly over the bridge of your nose.
- The most environmentally friendly masks are cloth masks that can be washed daily and re-used. The more layers of fabric, the more effective. A thin sheet of plastic between the layers increases resistance to viral penetration. Bandanas and neck fleeces do not offer much protection, however, and may even increase the dispersion of viral particles, breaking up large globules of saliva into smaller, lighter globlues .
- Professional masks are designed for specific purposes. For preventing your contamination of someone else, a surgical mask is superior to the others. To protect you from being contaminated, an N95 respirator works best. The problem with N95’s is that they are uncomfortable to wear, especially if engaged in physical activity or if they must be worn for long periods of time. The exhaust valve on the front of an N95 is designed for ease of ventilation, but it does not filter the air you breathe out, so wearing an N95 protects you but not others. The Chinese version of the N95 respirator is called a KN95. There have been concerns raised about the quality of these. For detailed information, see https://www.doximity.com/articles/030e6c60-af76-41b7-8b91-0eda81105d62
- Disposing of masks adds to the huge burden of waste we are already generating, and most professional masks are not biodegradable. They may look like paper but they actually support the growth of SARS-CoV-2 far longer than paper (7 days as opposed to 24 hours). Re-use your masks. Do not touch the front of the mask. Remove them carefully by lifting the loops behind your ears. Face masks that cannot be washed can be repeatedly sterilized at home in two ways, without compromising their filtration ability:
- Expose the mask to UV-C light for 30 minutes
- Steam heat the mask for 3 minutes. To do this, place a bowl of water in a microwave oven and cover it with some sort of mesh. Place the mask on top of the mesh. Run the microwave on high heat for 5 minutes, so that there will be at least 3 minutes of steam created. You cannot do this with a mask that contains metal or it will catch fire.
Here are links to some articles written to help you makes intelligent, personalized decisions about choice of masks:
Face masks aside, the old rules still apply: If you are sick, stay home and wear a surgical mask (if possible) around other people. When coughing or sneezing, cover your nose and mouth with your forearm or with a tissue and dispose of the tissue in a closed container. Avoid shaking hands. Physical distancing prevents viral spread; maintain awareness of your body in space.
AVOID THE HYPE ABOUT COPPER, ZINC AND SILVER. Copper and its alloys like bronze are the most potent of the anti-viral metals. However, several hours of copper exposure are needed to eliminate Covid-19, unlike cold viruses, which are killed in 60 seconds. Because the mechanisms by which different metals kill viruses tend to be similar, it is unlikely that metals like zinc or silver will be effective at killing Covid-19. Furthermore, the silver preparations tested in scientific studies are different from the colloidal silver that is sold in health food stores, so colloidal silver sprays cannot be relied upon for protection. High levels of zinc kill some corona viruses but are less effective than copper. Although some doctors advocate the use of zinc lozenges to prevent Covid-19, they are unlikely to help for 2 reasons: (1) the main site of viral entry is your nose, not your throat, and (2) zinc lozenges are unlikely to achieve time of contact or concentration needed to kill this virus. The main side effect of zinc is nausea, a symptom that plagues many people with Covid-19.
MOUTH WASHES. Some commercial mouth washes may kill or disable SARS-CoV-2. In addition In addition, povidone iodine (Betadyne) can be turned into an anti-viral mouthwash.  Because the major gateway through which the virus enters your body is the nose, it is unlikely that an oral rinse will have much impact or transmission. Salivary glands contain the only cells in the mouth with significant numbers of the two enzymes needed for viral cell entry.
THE HYGIENE HYPOTHESIS: FROM BOTH SIDES NOW
The Hygiene Hypothesis is a loosely formulated theory that the origin of modern diseases like allergies and autoimmune disorders derives from lack of exposure to germs in childhood. As I discussed in my book, The Allergy Solution, it’s a very incomplete and overly simplistic theory of everything. It’s also not particularly new or sophisticated. Growing up during the 1950’s, at a time when Madison Avenue was promoting the virtues of chemical cleanliness, I knew kids in school who would say, “My mom says you should eat an ounce of dirt every day.” In the case of Covid-19, pandemic deniers use it to demonize face masks, sanitation and physical distancing.
Historically, hygiene and health have been closely linked for about 5000 years. What’s changed over the past 70 years is the increasing reliance on toxic chemicals to sanitize our homes, clothes and lives. The burden of that toxic load is one theme of The Allergy Solution. But there is a kernel of truth to the Hygiene Hypothesis. It derives from the intimate and complex relationship between our cells and the tens of trillions of microbes that normally inhabit our bodies. I will deal with the facts and the details in two sections below: THE GUT MICROBIOME AND COVID-19 and TRAINED IMMUNITY, AN EMERGING CONCEPT. Meanwhile, don’t be intimidated by the Hygiene Hypothesis. In a pandemic, cleanliness can save your life.
NUTRITIONAL STRATEGIES FOR EVERY STAGE
- If you living in isolation with low risk of exposure, use this time to enhance ACE-2 resilience and immune balance. Before symptoms begin:
- Supplement with vitamin D, 1000 to 6000 IU/day, consume polyphenol-rich fruits, vegetables and herbs, avoid foods made with high fructose corn syrup and exercise regularly. The Fat Resistance Diet, a book that I wrote with the help of my son, Jonathan Galland, is filled with delicious recipes and meal plans that can help you meet those goals. It’s available at no charge for my patients, through my office.
- Supplement with flavonoids and other plant-derived polyphenols for 2 purposes
- Support ACE-2 activity
- Supplement with the anti-oxidant alpha lipoic acid
- Build up cellular levels to inhibit the action of 2 enzymes the virus relies on to enter your cells and spread through your tissues: Furin and 3CL-protease. These supplements also help your body control inflammation.
Substances include curcumin, luteolin, resveratrol, thymoquinone and quercetin. Ground flax seed, spearmint, sage, rosemary, thyme, oregano, and black tea may also be helpful.
- If you are at higher risk of exposure use all these and add elderberry fruit and Andrographis. This is also a good time to use the heparin nasal spray that I designed, available though a compounding pharmacy.
- If symptoms have already started, or once symptoms begin, do not take elderberry but continue to use or begin taking curcumin, luteolin, resveratrol, quercetin, and Andrographis. Also start baicaleinand Houttuynia cordata. If symptoms are severe or if they do not improve within 3 days, you must consult a medical professional.
- If you have been diagnosed with confirmed or suspected covid-19 but continue to be sick, and you have not already followed steps 1-3 above, then start them and add Astragalus membranosus. Beyond their anti-viral effects, these treatments are intended to promote restoration of ACE-2 activity and reverse the post-infectious inflammation that has been identified in people with Covid-19. Because Covid-19 produces changes to the gut microbiome that do not resolve when the infection clears, probiotics that target those changes may also be helpful.
If you are a patient and want more specific recommendations for prevention or treatment, please contact my office.
SECTIONS TO COME:
THE GUT MICROBIOME AND COVID-19
INSULIN, LEPTIN AND COVID-19
TRAINED IMMUNITY, AN EMERGING CONCEPT
MAST CELL ACTIVATION IN COVID-19
THE POST-VIRAL FATIGUE SYNDROME
OLD DRUGS, REPURPOSED – AN UPDATE
 What the cruise-ship outbreaks reveal about COVID-19. Mallapaty S. Nature. 2020 Apr;580(7801):18. doi: 10.1038/d41586-020-00885-w
Temporal dynamics in viral shedding and transmissibility of COVID-19.He X, Lau EHY, Wu P, Deng X, Wang J, Hao X, Lau YC, Wong JY, Guan Y, Tan X, Mo X, Chen Y, Liao B, Chen W, Hu F, Zhang Q, Zhong M, Wu Y, Zhao L, Zhang F, Cowling BJ, Li F, Leung GM. Nat Med. 2020May;26(5):672-675. doi: 10.1038/s41591-020-0869-5. Epub 2020 Apr 15.
 s: Argyropoulos KV, Serrano A, Hu J, Black M, Feng X, Shen G, Call M, KimMJ, Lytle A, Belovarac B, Vougiouklakis T, Lin LH, Moran U, Heguy A, Troxel A, Snuderl M, OsmanI, Cotzia P, Jour G, ASSOCIATION OF INITIAL VIRAL LOAD IN SARS-CoV-2 PATIENTS WITHOUTCOME AND SYMPTOMS, The American Journal of Pathology (2020), doi: https://doi.org/10.1016/j.ajpath.2020.07.001
 Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the NewYork City Area. Safiya Richardson, MD, MPH; Jamie S. Hirsch, MD,MA, MSB; Mangala Narasimhan, DO; JamesM. Crawford, MD, PhD; Thomas McGinn, MD, MPH; KarinaW. Davidson, PhD, MASc; and the Northwell COVID-19 Research ConsortiumJAMA. doi:10.1001/jama.2020.6775. Published online April 22, 2020. Corrected on April 24, 2020. Published online April 22, 2020. Corrected on April 24, 2020.
Turbulent Gas Clouds and Respiratory Pathogen EmissionsPotential Implications for Reducing Transmission of COVID-19. Lydia Bourouiba, PhD1JAMA. 2020;323(18):1837-1838. doi:10.1001/jama.2020.4756
The airbornelifetimeof small speech droplets and their potential importance in SARS-CoV-2 transmission. Stadnytskyi V1,Bax CE2,Bax A3,Anfinrud P3.Proc Natl Acad Sci U S A. 2020 May 13. pii: 202006874. doi: 10.1073/pnas.2006874117.
 Stability and infectivity of coronaviruses in inanimate environments. Shi-Yan Ren, Wen-Biao Wang, Ya-Guang Hao, Hao-Ran Zhang, Zhi-Chao Wang, Ye-Lin Chen, and Rong-Ding Gao. World J Clin Cases. 2020 Apr 26; 8(8): 1391–1399. Published online 2020 Apr 26. doi: 10.12998/wjcc.v8.i8.1391PMCID: PMC7190947. PMID: 32368532
 Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals. Liu, Y. et al. Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals. Nature https://doi.org/10.1038/s41586-020-2271-3 (2020)
 Dillon Adam, Peng Wu, Jessica Wong et al. Clustering and superspreading potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Hong Kong, 21 May 2020, PREPRINT (Version 1) available at Research Square [+https://doi.org/10.21203/rs.3.rs-29548/v1+] https://www.researchsquare.com/article/rs-29548/v1
 Shanna Ratnesar-Shumate, Gregory Williams, Brian Green, Melissa Krause, Brian Holland, Stewart Wood, Jordan Bohannon, Jeremy Boydston, Denise Freeburger, Idris Hooper, Katie Beck, John Yeager, Louis A Altamura, Jennifer Biryukov, Jason Yolitz, Michael Schuit, Victoria Wahl, Michael Hevey, Paul Dabisch, Simulated Sunlight Rapidly Inactivates SARS-CoV-2 on Surfaces, The Journal of Infectious Diseases, Volume 222, Issue 2, 15 July 2020, Pages 214–222, https://doi.org/10.1093/infdis/jiaa274
 Hou et al., SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract, Cell (2020), https://doi.org/10.1016/j.cell.2020.05.042
 Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives.Ritesh Tandon, Joshua S. Sharp, Fuming Zhang, Vitor H. Pomin, Nicole M. Ashpole, Dipanwita Mitra, Weihua Jin, Hao Liu, Poonam Sharma, Robert J. Linhardt
bioRxiv 2020.06.08.140236; doi: https://doi.org/10.1101/2020.06.08.140236
 Air, Surface Environmental, and Personal Protective Equipment Contamination by Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2) From a Symptomatic Patient. Ong SWX1, Tan YK2, Chia PY1, Lee TH1, Ng OT1, Wong MSY2, Marimuthu K1. JAMA. 2020Mar 4. doi: 10.1001/jama.2020.3227.
Maogui Hu, Hui Lin, Jinfeng Wang, Chengdong Xu, Andrew J Tatem, Bin Meng, Xin Zhang, Yifeng Liu, Pengda Wang, Guizhen Wu, Haiyong Xie, Shengjie Lai, The risk of COVID-19 transmission in train passengers: an epidemiological and modelling study, Clinical Infectious Diseases, ciaa1057, https://doi.org/10.1093/cid/ciaa1057
Covid-19 and the digestive system.Wong SH, Lui RN, Sung JJ. J Gastroenterol Hepatol. 2020 May;35(5):744-748. doi: 10.1111/jgh.15047. Epub 2020 Apr 19. PMID: 32215956
Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes.Zhang W, Du RH, Li B, Zheng XS, Yang XL, Hu B, Wang YY, Xiao GF, Yan B, Shi ZL, Zhou P. Emerg Microbes Infect. 2020 Feb 17;9(1):386-389. doi: 10.1080/22221751.2020.1729071. eCollection 2020. PMID: 32065057
Prolonged presence of SARS-CoV-2 viral RNA in faecal samples.Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, Yin H, Xiao Q, Tang Y, Qu X, Kuang L, Fang X, Mishra N, Lu J, Shan H, Jiang G, Huang X. Lancet Gastroenterol Hepatol. 2020 May;5(5):434-435. doi: 10.1016/S2468-1253(20)30083-2. Epub 2020 Mar 20. PMID: 32199469
COVID-19 Disease With Positive Fecal and Negative Pharyngeal and Sputum Viral Tests.Chen L, Lou J, Bai Y, Wang M. Am J Gastroenterol. 2020 May;115(5):790. doi: 10.14309/ajg.0000000000000610. PMID:32205644
Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding.Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, Guo Q, Sun X, Zhao D, Shen J, Zhang H, Liu H, Xia H, Tang J, Zhang K, Gong S. Nat Med. 2020 Apr;26(4):502-505. doi: 10.1038/s41591-020-0817-4. Epub 2020 Mar 13. PMID:32284613
Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible?Yeo C, Kaushal S, Yeo D. Lancet Gastroenterol Hepatol. 2020 Apr;5(4):335-337. doi: 10.1016/S2468-1253(20)30048-0. Epub 2020 Feb 20. PMID: 32087098
COVID-19: faecal-oral transmission?Hindson J. Nat Rev Gastroenterol Hepatol. 2020 May;17(5):259. doi: 10.1038/s41575-020-0295-
Persistent viral shedding of SARS-CoV-2 in faeces – a rapid review.Gupta S, Parker J, Smits S, Underwood J, Dolwani S. Colorectal Dis. 2020 May 17. doi: 10.1111/codi.15138. [Epub ahead of print] PMID: 32418307
 Memeo A, Loiero M. Thioctic acid and acetyl-L-carnitine in the treatment of sciatic pain caused by a herniated disc: a randomized, double-blind, comparative study.Clin Drug Investig. 2008;28(8):495-500. doi:10.2165/00044011-200828080-00004
 Ranieri M, Sciuscio M, Cortese AM, et al. The use of alpha-lipoic acid (ALA), gamma linolenic acid (GLA) and rehabilitation in the treatment of back pain: effect on health-related quality of life. Int J Immunopathol Pharmacol. 2009;22(3 Suppl):45-50. doi:10.1177/03946320090220S309
 Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-2040. doi:10.1182/blood.2020006000
 Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 doi: 10.1007/s00134-020-05991-x.
 Potus F, Mai V, Lebret M, et al. NOVEL INSIGHTS ON THE PULMONARY VASCULAR CONSEQUENCES OF COVID-19 [published online ahead of print, 2020 Jun 17]. Am J Physiol Lung Cell Mol Physiol. 2020;10.1152/ajplung.00195.2020. doi:10.1152/ajplung.00195.2020
 Archer SL, Sharp WW, Weir EK. Differentiating COVID-19 Pneumonia From Acute Respiratory Distress Syndrome and High Altitude Pulmonary Edema: Therapeutic Implications. Circulation. 2020;142(2):101-104. doi:10.1161/CIRCULATIONAHA.120.047915
 Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms.Troyer EA, Kohn JN, Hong S. Brain Behav Immun. 2020Apr 13. pii: S0889-1591(20)30489-X. doi: 10.1016/j.bbi.2020.04.027.
 Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network – United States, March–June 2020. MMWR Morb Mortal Wkly Rep. ePub: 24 July 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6930e1
 Immune cell profiling of COVID-19patients in the recovery stage by single-cell sequencing.Wen W, Su W, Tang H, Le W, Zhang X, Zheng Y, Liu X, Xie L, Li J, Ye J, Dong L, Cui X, Miao Y, Wang D, Dong J, Xiao C, Chen W, Wang H. Cell Discov. 2020May 4;6:31. doi: 10.1038/s41421-020-0168-9. eCollection 2020. PMID: 32377375
 Xu K, Chen Y, Yuan J, et al. Factors associated with prolonged viral RNA shedding in patients with COVID-19 [published online ahead of print, 2020 Apr 9]. Clin Infect Dis. 2020;ciaa351. doi:10.1093/cid/ciaa351
 Olivares-Gazca JC, Priesca-Marín JM, Ojeda-Laguna M, et al. INFUSION OF CONVALESCENT PLASMA IS ASSOCIATED WITH CLINICAL IMPROVEMENT IN CRITICALLY ILL PATIENTS WITH COVID-19: A PILOT STUDY. Rev Invest Clin. 2020;72(3):159-164. doi:10.24875/RIC.20000237
Robbiani, D.F., Gaebler, C., Muecksch, F. et al.Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature(2020). https://doi.org/10.1038/s41586-020-2456-9
 Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection.Jeffrey Seow, Carl Graham, Blair Merrick, Sam Acors, Kathryn J.A. Steel, Oliver Hemmings, Aoife O’Bryne, Neophytos Kouphou, Suzanne Pickering, Rui Galao, Gilberto Betancor, Harry D Wilson, Adrian W Signell, Helena Winstone, Claire Kerridge, Nigel Temperton, Luke Snell, Karen Bisnauthsing, Amelia Moore, Adrian Green, Lauren Martinez, Brielle Stokes, Johanna Honey, Alba Izquierdo-Barras, Gill Arbane, Amita Patel, Lorcan OConnell, Geraldine O Hara, Eithne MacMahon, Sam Douthwaite, Gaia Nebbia, Rahul Batra, Rocio Martinez-Nunez, Jonathan D. Edgeworth, Stuart J.D. Neil, Michael H. Malim, Katie Doores
medRxiv 2020.07.09.20148429; doi: https://doi.org/10.1101/2020.07.09.20148429
 Intrafamilial Exposure to SARS-CoV-2 Induces Cellular Immune Response without Seroconversion. Floriane Gallais, Aurelie Velay, Marie-Josee Wendling, Charlotte Nazon, Marialuisa Partisani, Jean Sibilia, Sophie Candon, Samira Fafi-Kremer
medRxiv 2020.06.21.20132449; doi: https://doi.org/10.1101/2020.06.21.20132449
 Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19.Takuya Sekine, André Perez-Potti, Olga Rivera-Ballesteros, Kristoffer Strålin, Jean-Baptiste Gorin, Annika Olsson, Sian Llewellyn-Lacey, Habiba Kamal, Gordana Bogdanovic, Sandra Muschiol, David J. Wullimann, Tobias Kammann, Johanna Emgård, Tiphaine Parrot, Elin Folkesson, Olav Rooyackers, Lars I. Eriksson, Anders Sönnerborg, Tobias Allander, Jan Albert, Morten Nielsen, Jonas Klingström, Sara Gredmark-Russ, Niklas K. Björkström, Johan K. Sandberg, David A. Price, Hans-Gustaf Ljunggren, Soo Aleman, Marcus Buggert, Karolinska COVID-19 Study Group
bioRxiv 2020.06.29.174888; doi: https://doi.org/10.1101/2020.06.29.174888
 Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China [published online ahead of print, 2020 Mar 12]. Clin Infect Dis. 2020;ciaa248. doi:10.1093/cid/ciaa248
 Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Jérôme Hadjadj, Nader Yatim, Laura Barnabei, Aurélien Corneau, Jeremy Boussier, Nikaïa Smith, Hélène Péré, Bruno Charbit, Vincent Bondet, Camille Chenevier-Gobeaux, Paul Breillat, Nicolas Carlier, Rémy Gauzit, Caroline Morbieu, Frédéric Pène, Nathalie Marin, Nicolas Roche, Tali-Anne Szwebel, Sarah H Merkling, Jean-Marc Treluyer, David Veyer, Luc Mouthon, Catherine Blanc, Pierre-Louis Tharaux, Flore Rozenberg, Alain Fischer, Darragh Duffy, Frédéric Rieux-Laucat, Solen Kernéis, Benjamin Terrier. Published Online 13 Jul 2020. DOI: 10.1126/science.abc6027
 Type I interferon susceptibility distinguishes SARS-CoV-2 from SARS-CoV. Kumari G. Lokugamage, Adam Hage, Maren de Vries, Ana M. Valero-Jimenez, Craig Schindewolf, Meike Dittmann, Ricardo Rajsbaum, Vineet D. Menachery
bioRxiv 2020.03.07.982264; doi: https://doi.org/10.1101/2020.03.07.982264
Sajuthi SP, DeFord P, Jackson ND, et al. Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium. Preprint. bioRxiv. 2020;2020.04.09.034454. Published 2020 Apr 10. doi:10.1101/2020.04.09.034454
 CellPress Volume 27, Issue 6, 10 June 2020, Pages 883-890.e2.Heightened Innate Immune Responses in the Respiratory Tract of COVID-19 Patients Zhuo Zhou 1214 Lili Ren 2314 Li Zhang 414 Jiaxin Zhong 4514 Yan Xiao 214 Zhilong Jia 6 Li Guo 2 Jing Yang 45 Chun Wang 45 Shuai Jiang 4 Donghong Yang 7 Guoliang Zhang 8 Hongru Li 9 Fuhui Chen 10 Yu Xu 7 Mingwei Chen 11 Zhancheng Gao 7 Jian Yang 2…Jianwei Wang 2315
 Ma A, Cheng J, Yang J, Dong M, Liao X, Kang Y. Neutrophil-to-lymphocyte ratio as a predictive biomarker for moderate-severe ARDS in severe COVID-19 patients. Crit Care. 2020;24(1):288. Published 2020 Jun 5. doi:10.1186/s13054-020-03007-0
 Theoharides TC, Conti P. Dexamethasone for COVID-19? Not so fast [published online ahead of print, 2020 Jun 4]. J Biol Regul Homeost Agents. 2020;34(3):10.23812/20-EDITORIAL_1-5. doi:10.23812/20-EDITORIAL_1-5
 Razzaghi H, Wang Y, Lu H, et al. Estimated County-Level Prevalence of Selected Underlying Medical Conditions Associated with Increased Risk for Severe COVID-19 Illness – United States, 2018. MMWR Morb Mortal Wkly Rep 2020;69:945–950. DOI: http://dx.doi.org/10.15585/mmwr.mm6929a1
medRxiv 2020.05.01.20087965; doi: https://doi.org/10.1101/2020.05.01.20087965
 SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. Thomas Mandel Clausen etal. bioRxiv 2020.07.14.201616; doi: https://doi.org/10.1101/2020.07.14.201616
 Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions So YoungKim, et al. Antiviral Research 181 (2020) 104873
 ACE2-independent interaction of SARS-CoV-2 spike protein to human epithelial cells can be inhibited by unfractionated heparin. Lynda J. Partridge et al. bioRxiv 2020.05.21.107870; doi: https://doi.org/10.1101/2020.05.21.107870
 Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence.. van Haren FMP et al. Crit Care. 2020;24(1):454. Published 2020 Jul 22. doi:10.1186/s13054-020-03148-2
 Vidricaire G, Denault JB, Leduc R (1993) Characterization of a secreted form of human furin endoprotease. Biochem Biophys Res Commun 195: 1011–1018
 Anwarul Hasan, Bilal Ahamad Paray, Arif Hussain, Fikry Ali Qadir, Farnoosh Attar, Falah Mohammad Aziz, Majid Sharifi, Hossein Derakhshankhah, Behnam Rasti, Masoumeh Mehrabi, Koorosh Shahpasand, Ali Akbar Saboury & Mojtaba Falahati(2020)A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin,Journal of Biomolecular Structure and Dynamics,DOI: 10.1080/07391102.2020.1754293
 Wu C, Yang Y, Liu Y, Zhang P, Wang Y, Wang Q, Xu Y, Li M, Zheng M, Chen L et al (2020b) Furin, a potential therapeutic target for COVID-19. chinaRxiv
 Low-cost measurement of facemask efficacy for filtering expelled droplets during speech.By Emma P. Fischer, Martin C. Fischer, David Grass, Isaac Henrion, Warren S. Warren, Eric Westman. Published Online07 Aug 2020eabd3083