CORONAVIRUS GUIDEBOOK

December 22, 2020

NOTE: Approval of vaccines for prevention of Covid-19 is generating enthusiasm and pushback. I’ve summarized my present thoughts about the vaccines toward the end of this guide THERAPEUTIC PROFILES. As with everything else about Covid-19, the story is dynamic and may change with new information.

The Covid-19 pandemic has brought the world to a standstill for 3 reasons:

  1. It is highly contagious, spreading readily within groups of people [1]. As discussed below, new mutations are increasing the speed with which the virus spreads from person to person.
  2. Covid-19 is often spread by people who are who are asymptomatic [2]. In fact, the virus is most contagious before or soon after onset of symptoms [3][4]. The ability of asymptomatic people to spread the infection raises concerns about the impact of vaccines on community transmission (discussed below under VACCINES).
  3. Although 80% of infected people have no symptoms at all or experience a trivial illness, about 3.5% 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 [5]. By late summer 2020, the hospital mortality rate of Covid-19 had dropped to 7.6%, which is still high (discussed below in RATE). In early December, 2020, Covid-19 because the leading cause of death in the United States. It is the third leading cause of death in the U. S. for the year 2020, and is likely to continue in that same position during 2021, whatever changes are created by mass vaccination.

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. People who have recovered from the infection often show long term deficits in cognitive function, even after relatively mild disease.[7]

I began posting this guide to Covid-19 at the end of February 2020, 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.

THE VIRUS

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. Within 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.

Since its apperance in Wuhan, the virus has continued to mutate. The dominant mutation called G614D, which was first noted in Europe and then spread throughout the Western hemisphere and back to Asia, is believed to make the virus more contagious, but not deadly[8]. Increased transmissibility may explain why the rate of secondary spread among household contacts was 10.3% in China [9] but 35% in the U.S [10] Increasing transmissibility helps to explain why the main venues for transmission have moved from large superspreader events (which were the dominant mode in Hong Kong [11]) to small indoor gatherings, which are not dominant in the U.S. A set of new mutations reported from the United Kingdom may be further increasing the speed of transmission.

TRANSMISSION

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 [12]. 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 [13], 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 [14]. A study from Wuhan found aerosolized SARS-CoV-2 in medical staff areas and unventilated bathrooms [15]. In the cold, stale air of a meat processing plant, the virus was able to infect people 26 feet away from its source [16].

The role of airborne aerosols in the spread of Covid-19 has been controversial, in part because the viral load of the smallest droplets is much lower than the viral load of larger droplets[17]. After reviewing detailed data from several well-studied clusters, I have concluded that airborne aerosols play a significant role in transmission, a view shared by many scientists. Physical distancing may not protect against aerosol spread, but masks can be very effective [18] (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 [19]. 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. Open 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[20]. Winter conditions double the time required. Clusters of cases related to backyard barbecues and other 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 [22]. Having multiplied in the nose, SARS-CoV-2 is in a strong position to invade both the brain[23] and the blood vessels. The initial viral load in the nose is a key factor determining the severity of infection[24], so that covering your nose with a mask – almost any mask – may protect you, in addition to preventing spread to others [25] (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 [26][27][28][29][30] (One nasal spray presently available is discussed below in THERAPEUTIC PROFILES/HEPARIN NASAL SPRAY).

Airborne virus will settle on solid surfaces and air vents and remain viable on these surfaces for varying periods of time [31].  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 [32]. 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 [33], appearing in bowel movements. Flushing a toilet with the lid open may then allow viral particles to become airborne. The virus frequently contaminates sewage. It persists in stool when respiratory swabs are negative [34][35][36][37].

A small study demonstrated that when found in stool the virus is not only viable but infectious [38] Food-borne or water-borne infection is possible but still unproven [39][40][41]. 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 [42]. A report from China described a shipment of shrimp in which the packaging was contaminated with SARS-CoV-2 (the shrimp itself was not) [43]. Another report found chicken wings to be contaminated with SARS-CoV-2 [44], but the infectivity of the virus on food has not been established.

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 [45]. 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 [46]. 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 [47], possibly in combination with gamma-linolenic acid (GLA(, which is found in evening primrose and borage seed oils [48]. (More on alpha-lipoic acid in ACE-2  ENHANCEMENT).

People recovering from loss of smell (a condition called anosmia) sometimes develop a distorted sense of smell that varies and fluctuates in severity and in the nature of the distortions that occur. This is called parosmia. Research into parosmia may shed light on the origin of post-infectious neurological symptoms, which are fairly common in people recovering from Covid-19.  The research suggests the following explanation: as damaged nerves begin to heal, they form new connections (synapses) that relay information between different parts of the brain. When first formed these synapses may present confusing information that creates baffling but intermittent neurological symptoms[49]. In the case of parosmia, training through aroma therapy may enhance recovery by supporting a phenomenon called neuroplasticity[50]. It is possible that other approaches to supporting neuroplasticity may speed recovery of other symptoms of longhaul Covid.

 

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 [51]. 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 [52]. 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 biology of severe or late-stage Covid-19 may be different from the biology of early stage infection, which is the subject of this guide.

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 [53]. This should not be treated with mechanical ventilation but by high dose oxygen and by measures that improve the regulation of blood flow [54]. 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 [55]. 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. [56] 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 [57]. 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 [58]Persistent inflammation is one possible cause of Phase 4 illness. Other factors that may contribute include subtle damage to the heart or nervous system, mild scarring (fibrosis) of the lungs, changes to the gut microbiome, or persisting depletion of the enzyme ACE2, which is discussed below under CORONAVIRUS BIOLOGY.

Most people remain infectious for about 9 days after the onset of symptoms[59] but may shed the virus in secretions for more than two weeks[60].   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.

 

IMMUNITY

Three important questions about immunity impact prevention and treatment of Covid-19:

  1. What aspects of the immune system can prevent serious infection?
  2. How does the immune response affect people who are sick?
  3. 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. A small study from Mt. Sinai Hospital in New York found that the death rate from Covid-19 among hospitalized patients with an underlying immune deficiency was about twice that of other patients [61]. In contrast, one report from Italy found that people receiving immune suppressive drugs for organ transplantation were not at increased risk of severe infection[62] and a study from New York University found no significant difference in outcome when comparing hospitalized patients with Covid-19 who were HIV positive or negative[63]. In Britain, HIV-positive patients under the age of 50 who were hospitalized with Covid-19 had a much higher mortality rate than patients without HIV, but older patients with HIV had a reduced mortality rate.[64]

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.[65]  Many people infected with SARS-CoV-2 do not develop antibodies, however[66], and among those who do, antibody levels may drop sharply after 20—30 days[67]. 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. The nature of the antibodies produced impacts the severity of illness. People with milder illness tend to make antibodies to the viral spike protein that can inhibit entry of the virus into cells, whereas people who are sicker tend to make other types of antibodies that may be less effective.[68] Many different types of auto-antibodies have been found in people with Covid-19.[69] Auto-antibodies attack the cells of your own body, rather than attacking the virus. For these people, Covid-19 can act like an autoimmune disease. The most dangerous auto-antibodies are those that inactivate interferons, the anti-viral proteins of your innate immune response[70]. These incapacitate your body’s first line of defense against viral infection.

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[71] [72]. 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.[73] 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[74]. 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 [75].

Some components of the innate immune system are able to prevent infection or reduce severity of disease [76]. SARS-CoV-2 is readily inactivated by proteins called Type 1 Interferons, which are produced by cells of the innate immune system [77]. But the virus is uniquely able to fool its human host into producing very little Type 1 Interferon, so even someone with a strong innate immune response may lack this first line antiviral defense[78]. In people with life-threatening illness, as described above, the virus even provokes the production of auto-antibodies that inactive whatever interferon is produced. The deficit of type 1 interferons allows other components of the innate immune system to increase inflammation and tissue damage[79] [80]

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. [81] Mast cells are the main source of cytokines in the lungs [82]. 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 [83]. 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)

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.  Inhibiting the viral enzymes that create its stealth tactics is one approach,  discussed below in CORONAVIRUS BIOLOGY and INTEGRATED VIRUS MANAGEMENT.

RATES

[I keep hoping that this section won’t be necessary, but the misinformation about natural herd immunity keeps re-circulating.]

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 [84].

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 [85].

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. [86] 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. [87] 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 [88] Systematic screening of 1800 residents of Miami-Dade County in late April found that 6% of people had been infected with SARS-CoV-2[89]. If that number is applied to the entire county, the infection fatality rate there would have been about 0.3%.

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 was quite a bit lower than it had been 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 developed more experience with this disease and were 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[90] [91]. (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 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 much higher than the number of confirmed cases. At present, there are millions 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.

A note on herd immunity: the Swedish experiment, intended to allow the virus to spread among healthy, low risk people while attempting to protect those at high risk, has failed. Not only has the population fatality rate from Covid-19  been 5 to 10 times greater in Sweden than it was in other Scandinavian countries, the second wave has washed over Sweden this fall with the same ferocity as most other nations in Europe. Although a third of Swedes now have antibodies to Covid-19, there is no evidence of herd immunity. At San Quentin Penitentiary, the spread of Covid-19 was not controlled until 60% of the population had been infected[92].

CORONAVIRUS BIOLOGY

Even a successful global vaccination campaign will not remove the need to  understand the complex biology of SARS-CoV-2. I have relied on this biology in designing and refining 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. 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. For rapid spread, each of these four steps is essential. Addressing them is the core of an integrated management approach to stopping Covid-19 at the cellular level.

There are four human molecules that, working together, enable SARS-CoV-2 to quickly and efficiently 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’s external membrane (called the plasma membrane). Their names are heparan, 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.  

  • Step 1. Heparan is a complex sugar that coats the outside of all human cells. A derivative, purified heparin, is used in medicine as an anticoagulant drug, given by injection. The viral spike protein of SARS-CoV-2 sticks to heparan on the cell membrane, through a powerful electrical attraction [93]. Heparan holds the virus in place [94] 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 [95].
  • Researchers have proposed administering heparin through a nebulizer, inhaled into the lungs, to limit viral spread in people who are sick [96].
  • 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 below under HEPARIN NASAL SPRAY). An Israeli pharmaceutical company has created a nasal spray called Tafflix, with a similar function, to neutralize the viral spike protein by applying an acidic gel inside the nose; use of their product reduced the incidence of new cases of covid-19 by 78% among people praying together for 7 hours a day during 2 days of Rosh Hoshanah.[97]

 

  • Step 2. Furin, like heparan, coats all human cells[98], but unlike heparan, it is an enzyme. Its role in Covid-19 is to split the viral spike protein in two, so that one part fits tightly into its cellular receptor, ACE-2, the way a key fits into a lock[99]. Without priming by furin, the viral spike protein forms a very weak attachment to the cellular receptor and the entry of virus into cells becomes slow and inefficient. The place on the viral spike protein that sticks to heparan (the heparan binding site) overlaps the place where it’s split by furin (the furin cleavage site). This relationship has enabled the pandemic, because it dramatically enhances the speed with which the virus enters human cells. .

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. The presently dominant pandemic mutation, G614D, mentioned above, allows the viral spike protein to rotate so that the furin cleavage site is more exposed.

  • 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 [100]. 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 and anti-viral effects that are separate from furin inhibition. Anti-inflammatory effects 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 called LUTEOLIN).

The newest strain of SARS-CoV-2, which is ravaging Great Britain at the moment, has 23 mutations, one of which scares scientists because it involves the next step in viral cell entry, a tiny segment of the viral spike protein adjacent to the furin cleavage site, called the receptor binding domain.

 

  • Step 3. ACE-2, a protein embedded in the human cell membrane, is the centerpiece for viral entry, so it’s called the cellular receptor and it attaches to the receptor binding domain of the viral spike protein. 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 uses ACE-2 to enter cells, 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.

Some scientists are attempting to develop drugs that prevent the viral spike protein from attaching to ACE-2. There is a natural product that does just that: quercetin, a bioflavonoid found in onions, apples and other fruits and vegetables. Quercetin is able to insert itself between ACE-2 and the receptor binding domain of the viral spike protein[101]. It’s like a friendly bystander breaking up a fight. A small clinical trial from Turkey showed that health care workers taking quercetin 250 mg twice a day, along with vitamin C and bromelain (an enzyme found in pineapple stem) had a 92% reduction in acquiring antibodies to SARS-CoV-2, compared to health workers not taking quercetin[102]. This implies that these workers were far less likely to have become infected during the trial. Quercetin was considered to be the active ingredient. The intended role of vitamin C and bromelain was to increase quercetin absorption. The results of this study would be far more exciting if the participants had been randomly assigned to take quercetin or not, but instead   they self-selected what they would do, which leaves considerable room for bias.

I have long advocated quercetin for people at risk of Covid-19, as have many other physicians and scientists, but very recent research has led me to modify my recommendations. In blocking viral attachment, quercetin also inactivates ACE 2[103], an undesirable effect.  In this laboratory study, ACE-2 was only exposed to quercetin once. It’s possible that with repeated exposure, the body would actually produce more ACE-2, reversing the blockade, an interaction reported between quercetin and a related enzyme called ACE[104].

 My present strategy is to encourage quercetin use as part of a preventive program in people at high risk of exposure, but not among people who already have symptoms. Once the infection occurs, you need all the ACE-2 activity your cells can muster.

Support for ACE-2 and its functions is critical for reducing severity of Covid-19. The details are described in the section called ACE-2 ENHANCEMENT.

 

  • Step 4. 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 fuse with the cell membrane. The cells that the virus can enter most quickly and efficiently 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 lining of the heart and blood vessels, testicles and the small and large intestines. In these cells, it appears that the rate-limiting step for viral entry is the level of TMPRSS2, not the level of ACE-2, because TMPRSS2 speeds the rate of cell entry about one hundred fold. Depending on the type of cell, inhibition of TMPRSS2 can reduces viral entry by over 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, according to one study, 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[105]. The effect of IL-13 may explain the results of large studies from South Korea, which found that people with non-allergic asthma were more than 4 times as likely to develop severe complications of Covid-19 than people without asthma[106] and that those who had experienced a flare-up of asthma within the past year had almost 3 times the fatality rate if hospitalized with Covid-19[107]. [Other studies have shown that asthmatics are less likely to develop Covid-19. I believe that is due to asthmatics being extra cautious about exposure and also because many take inhaled steroids, which appear to have a protective effect].

  • The good news: Inhibitors of TMPRSS2 exist, although none are readily available in the U.S. The safest of these is a cough medicine called bromhexine, which has been used in Europe, Asia and Latin America for decades. A randomized clinical trial in Iran found that addition of bromhexine to usual care at the time of hospitalization produced an 80% reduction in ICU admissions and the need for mechanical ventilation and reduced the death rate from 12% to zero[108].
  • 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, thymoquinone, 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 below).

In people who are sick with Covid-19, inflammation may create additional pathways through which the virus spreads from cell to cell. For acquiring the initial infection, however, the Front Four prevail.

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.  Its first act is to create a large complex poly-protein that rapidly splits itself into 16 smaller structures called non-structural proteins (nsp’s) that function to evade your immune system, punch holes in your cells and enable the production of structural proteins. One of these, nsp-5, also known as the main protease or 3CL-protease, is essential for viral spreading because it acts like a scissor to break out 12 of the other nsp’s. It works in tandem with nsp-3, also called papain-line protease, which releases two other segments of the poly-protein.  Because 3-CL protease is so essential for viral growth, 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, especially the flavonoids luteolin and quercetin. You’ve already met them both. 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, not only decreases synthesis of TMPRSS2, it acts to inhibit the corona virus 3CL protease.
  • 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 cordata an 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.

ACE-2 ENHANCEMENT

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.  The principles of an anti-inflammatory diet of the kind that supports ACE-2 activity, are described in my book, The Fat Resistance Diet, written to help with weight loss but designed to combat inflammation for people without a weight problem.

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 the 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). Alpha-lipoic acid is most useful during states of inflammation, in which it inhibits the shedding of ACE 2 from cells.

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 about the role of ACE-2 in Covid-19 created some pushback 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. ACE-2 is also shed from the surf ace of cells and circulates in blood. When the rate of shedding is high, the levels of ACE2 on the cell surface go down.

Whether bound to cells or 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[109]. The names are not important. What is important is that people who are critically ill with Covid-19 have highly elevated levels of both 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.

And elevated ACE-2 in blood may indicate loss of ACE-2 in cells.

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 South Florida and University of Pennsylvania are conducting clinical trials of Ang 1-7 to treat or reverse complications of Covid-19 in hospitalized patients. More about Ang 1-7 in THERAPEUTIC PROFILES.

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: baicalein from Scutellaria baicalensis (receiving its third honorable mention) and Astragalus membranaceus (the active components are called Astragalus root polysaccharides). Their potential use is described below in INTEGRATED VIRAL MANAGEMENT.

 

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

RISK ASSESSMENT

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 encounter 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 may 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. Although rare, repeat infections with Covid-19 are emerging; half their severity is greater than those of the first infection. If you have persisting symptoms, they are likely to decrease over time. Depending on the nature of your symptoms, there are self-help treatments that may help you restore your health. Voice training, for example, may help with breathlessness.[110]

ANTI-VIRAL HYGIENE

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.  SARS-CoV-2 can survive for 9 hours on human skin, but is rapidly inactivated when hand sanitizer containing 80% alcohol is applied[111]. Soap is also an ideal anti-coronavirus cleanser, because it destroys the virus’s protective envelope. I don’t recommend the use of antibacterial soap; the antibacterial components may not enhance viral killing and can 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[112]. You can search it at:

https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-methanol#products

The FDA has cautioned against contamination of hand sanitizers with 1-propanol, which may cause sedation[113].

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.

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.

Live Sars-CoV-2 may survive on frozen meat or fish for 3 weeks, so handle frozen food with care.

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[114].  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. Some reports indicate that bandanas and neck fleeces do not offer much protection and might even increase the dispersion of viral particles, breaking up large globules of saliva into smaller, lighter globules[115] [116]. A study from the University of Georgia, however, found that neck gaiters composed of a single piecfe of fabric decreased droplet spread by 77% and multilayered gaiters could decreae droplet spread by 96%. [117]
  • Professional masks are designed for specific purposes. For preventing your contamination of someone else, a surgical mask is superior to most 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 with an exhaust valve 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:
https://www.wired.com/story/scientists-put-masks-to-the-test-with-an-iphone-and-a-laser/
https://www.popsci.com/story/diy/make-diy-face-masks/
https://www.aol.com/article/lifestyle/2020/03/24/how-to-make-a-face-mask-that-is-effective-against-coronavirus/23960274/
https://www.nbcnews.com/health/health-news/making-your-own-face-mask-some-fabrics-work-better-others-n1175966
https://slate.com/technology/2020/04/comprehensive-guide-masks.html?v

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 SARS-CoV-2, 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, povidone iodine (Betadyne) can be turned into an anti-viral mouthwash.[118] 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. 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:
  1. 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.
  2. Supplement with flavonoids and other plant-derived polyphenols for 2 purposes
  1. Support ACE-2 activity
  2. Supplement with the anti-oxidant alpha lipoic acid
  3. 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, quercetin 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 or quercetin, but continue to use or begin taking curcumin, resveratrol, and Andrographis. Also start baicalein and 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 membranaceus. 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.

 

THERAPEUTIC PROFILES

VACCINES

As of December 17, 2020, The New York Times Coronavirus Vaccine Tracker listed 63 vaccines in human trials, and at least 85 preclinical vaccines were under investigation in animals. All the attention in the U.S. press has gone to two vaccines developed by U.S. companies, Pfizer and Moderna, and a U.K.-based vaccine developed by Oxford University and AstraZeneca. Pfizer and Oxford results have been published in peer-reviewed medical journals .  (https://doi.org/10.1016/S0140-6736(20)32661-1)(https://www.nejm.org/doi/full/10.1056/NEJMoa2034577). Pfizer and Moderna use a new technology, which is nicely described in this link. https://apple.news/AdDn5HRKuTraUHhcfNtWCqQ.

There are 3 important questions that we need covid vaccine trials to answer:

  1. How effective is this specific vaccine at preventing or reducing the severity of disease?
  2. How effective is this vaccine at preventing spread of the virus?
  3. What are the side effects?

It appears that all 3 vaccines are highly effective at decreasing the severity of infection. We don’t know how well they prevent viral transmission.  The only research group that’s attempted to answer that question is the Oxford/Astra team. Although the Oxford vaccine reduced the rate of sickness by about 70%, there was almost no reduction in the rate of asymptomatic infection, which was 1.2% in the vaccine group and 1.3% in the control group . The vaccine therefore decreased the incidence of covid-19, the disease, but had a much smaller impact on transmissibility of the viral infection itself. https://apple.news/Am4uh_lzBQXSmpKmtXNOr0A

Here’s why this is important:

If vaccination does not stop asymptomatic spread, it may not create herd immunity. It is even possible that the rate of asymptomatic infection in the population will increase over the first several months of 2021 and those who have not been vaccinated will experience a greater risk of exposure and infection, increasing rather than decreasing the need for other preventive measures. Your decision whether to take the vaccine or not should consider the increased risk associated with being unvaccinated.

As for side effects, to evaluate them, you need the details of the clinical trials, which are not usually reported in the media.

The Pfizer vaccine was tested in adults and adolescents over the age of 16, including people with chronic underlying medical conditions that were stable. Specifically excluded were people described as immune compromised, people taking immune suppressive drugs, children, pregnant women and people with chronic conditions that were not stable. Also excluded were people with a history of severe allergic reactions (anaphylaxis). Conclusions reached from this trial may not apply to groups of people who were specifically excluded from the trial.

There were about 5000 people with a history of allergies who received the Pfizer vaccine and there were no reports of serious allergic reactions. As this vaccine has been administered to health care workers in the U.K. and the U.S., reports of severe allergic reactions (anaphylaxis) have emerged, so that the FDA and the British are advising people with a history of anaphylaxis to not receive this vaccine. A likely source of the allergic reactions is polyethylene glycol used as a carrier in the vaccine. https://childrenshealthdefense.org/defender/fda-investigates-reactions-pfizer-covid-vaccine-healthcare-workers-hospitalized/

Other adverse reactions to the Pfizer vaccine occurred frequently in the clinical trial. Systemic reactions like fever, headache and fatigue were more common in people under age 55 than in those over 55 and were more frequent after the second dose than the first.  This suggests that a stronger immune response to the vaccine was responsible for a higher frequency of adverse events.  Severe fatigue was observed in 4% of vaccine recipients and lasted for up to 2 weeks. Safety of the vaccine was determined for a follow up period of two months.

In the Oxford/Astra trial, the vaccine was administered only to healthy adults with no reported underlying medical conditions. Most were between 18 and 55 years old. Instead of a placebo for comparison, the control group received another vaccine, one for preventing meningitis. This may be important when considering side effects.

Three patients out of about 13,000 developed a rare autoimmune disorder called transverse myelitis, which is inflammation of the spinal cord. One patient had received the meningitis vaccine and two had received the covid vaccine. One of those two had an unreported underlying condition, multiple sclerosis, which by itself increases the risk of transverse myelitis. The prevalence of transverse myelitis in people with M.S. or in the general population is very low, under 5 people per million in the general population and under 25 per million among people with M.S. The rate of transverse myelitis after the Oxford/Astra vaccine was about 330 cases per million, which is between a hundred and 500 times greater than would be expected.

Based on the available information, extreme caution should be used by people with allergic or autoimmune diseases who are considering vaccination for covid-19.

There is no doubt that covid vaccination will save lives and keep many people from needing hospitalization. More data on safety and efficacy should be available by March or April, when the vaccine becomes available for the general population.  At that time I hope to be able to clarify recommendations for its use among my patients with autoimmune and allergic disorders.

HEPARIN NASAL SPRAY

In my search for strategies that can limit Covid-19, I’ve discovered a potential role for non-toxic anti-viral nasal sprays. The cells that line your nose are the main portal of entry for the virus into your body. Blocking cellular entry in the nose may prevent transmission or at least reduce the initial viral load, which is an important factor in severity of illness. Laboratory evidence suggests several candidate compounds.

The one that is readily available now, because it’s already approved by the FDA for other uses, is low dose heparin, which is described below. It is safe, simple, stable and relatively inexpensive. You may want to consider the use of nasal heparin during situations in which you are potentially exposed to the virus, including work, travel, school or social encounters. Heparin does not have long-term preventive benefits. It should be used as needed for potential exposure, but is safe enough to be taken daily for extended periods of time. If this approach interests you, please read the document below and contact my office.

Heparin is an anticoagulant, administered by injection to prevent and treat blood clots. It is also the derivative of natural substance called heparan sulfate, which is found on the membranes of cells throughout the body. Heparan sulfate is part of a cellular coating called the glycocalix, found on the outside of all human cells.

SARS-CoV-2, the virus that causes Covid-19, enters human cells through a multistep process in which a prong on the surface of the virus (the viral spike protein) attaches to an enzyme called ACE-2, which is embedded in the membranes of certain cells. Heparan is essential for this attachment, because heparan on the outside of the cell membrane holds the viral spike protein in place[119]. Without this binding, the virus is not able to find the ACE2 molecules that it needs for cell entry[120]. Free heparin, administered as a medication, can act as a decoy, attaching to the viral spike protein so that the virus is not able to attach to the heparan that is located on the cell membrane[121]. This decoy binding is very tight and irreversible and occurs at extremely low concentrations of heparin[122].

Injected heparin is widely used to treat or prevent blood clots in hospitalized patients with Covid-19, where it saves lives and is becoming standard treatment. Inhaled heparin, given at high doses by nebulizer, has been used to treat the acute respiratory distress syndrome (ARDS), which is a complication of Covid-19 and other diseases. The purpose of inhaled heparin is to prevent widespread clotting in the small blood vessels of the lungs, which is a feature of ARDS. Inhaled heparin has no significant effect on systemic coagulation, even at high doses[123].

The goal of nasal heparin is to prevent attachment of the SARS-CoV-2 spike protein to ACE-2, neutralizing the virus. The dose needed for this effect is much lower than the dose needed to inhibit blood clots, so it should be easy to attain and there should be no systemic anticoagulant effect of the nasal spray. There may, however, be a local anticoagulant effect, limited to the inside of your nose and perhaps your mouth.

The lining of your nose is the major gateway through which the virus enters your body. Here is the highest co-concentration of all the factors needed for SARS-CoV-2 to enter cells. Your nose then acts like an incubator in which the virus multiplies and from which it is inhaled into your lungs[124]. Preventing or limiting viral entry into your nose has the potential to prevent or reduce systemic disease. An Israeli pharma company has developed and tested a product with a similar purpose, neutralizing the positive charge on the viral spike protein with an acidic compound, and demonstrated a 75% reduction in transmission of covid-19 among people using their nasal spray while praying together for 2 days of Rosh Hoshanah[125].

Heparin nasal spray can be compound by any pharmacy or made in aphysician’s office. It will require a prescription. The nasal spray consists of a low dose of heparin dissolved in salt water. It should be sprayed into each nostril soon before and soon after a potential exposure to Covid-19 . It can be used daily, every 4 hours, if you have continuous or repeated exposure to Covid-19. The solution has a shelf life at room temperature of about a year. Each bottle contains 300 sprays.

The blood level at which heparin produces anticoagulation is 0.4 to 0.7 units/ml. The concentration in the spray is 10 units/ml, which should be more than enough to saturate the virus, even when diluted by nasal secretions. The entire spray bottle contains only 300 units of heparin. When given by inhalation in hospitals, the dose administered each time is 25,000 units. Because it has to cover only a small surface area, the heparin nasal spray provides a very low dose for your body, but a relatively high concentration in your nose.

Commercial heparin is derived from pork intestine, so do not use the spray if you are allergic to pork. Pseudo-allergic reactions to heparin may also occur. If you experience swelling or difficulty breathing, discontinue the use of the nasal spray and contact me. Intravenous heparin is administered to tens of millions of patients a year, mostly in hospitals, and with very few side effects. Do not use heparin if you have or are prone to nose bleeds and discontinue heparin several days before any dental surgery or ENT procedure.

LUTEOLIN

In laboratory studies, luteolin stops the growth and spread of many different viruses by inhibiting enzymes these viruses need to invade cells and replicate. These include:

Luteolin’s effect on dengue virus is due to its ability to inhibit an enzyme called furin. Furin exists on the outside of all human cells and is needed for many viruses to enter cells. Among the viruses that depend on furin for cell entry is SARS-CoV2, the virus that causes Covid-19[133] [134]. Luteolin also inhibits an enzyme called 3CL protease, which enables corona viruses to spread throughout the body[135].

In addition, luteolin can damp down the inflammatory response to viral infection, which may decrease severity of disease[136]. Luteolin’s anti-inflammatory effects decrease lung injury caused by the epidemic H1N1 flu virus in mice[137].

Because of its anti-viral and anti-inflammatory effects, luteolin has been proposed as a treatment to mitigate the effects of Covid-19[138] [139].  Like thymoquinone, luteolin inhibits activity of interleulin-13 (IL-13)[140] a protein that has been implicated in severity of Covid-19 among hospitalized patients[141].

The anti-inflammatory effects of luteolin are synergistic with those of curcumin[142].

CURCUMIN

Like luteolin, curcumin has shown anti-viral and anti-inflammatory effects in many laboratory studies. Most important is the ability of curcumin to diminish the inflammatory response provoked by viral infection and its synergy with thymoquinone and luteolin in controlling inflammation.

In the lungs, curcumin reduces tissue damage and severity of pneumonia caused by influenza virus[143] [144].  Curcumin prevents scarring of the lungs following the Acute Respiratory Distress Syndrome (ARDS) caused by severe viral pneumonia[145] .

Curcumin also protects the heart from coxsackie virus infection[146] and genital tissue from damage caused by herpes simplex virus (HSV). [147] Curcumin also stops the growth of HSV-1 and HSV-2[148].

The beneficil effects of curcumin are synergistic with those of  luteolin[149] and thymoquinone[150][151]. In addition, thymoquinone and curcumin show synergistic anti-viral effects against an avian influenza virus[152].

Curcumin has been proposed as a treatment for reducing the severity of Covid-19 by multiple mechanisms, including its anti-inflammatory effects but also its ability to interact with 30 different proteins that viruses use to enter human cells, damage those cells, replicate and spread to other cells. [153] [154] Two novel mechanisms by which curcumin can reduce severity of Covid-19 have been demonstrated:  induction of a protective enzyme called hemoxygenase (HO-1)[155] and binding to the SARS-CoV-2 viral spike protein, preventing the virus from attaching to its human cellular receptor[156].

THYMOQUINONE

Black cumin seed has been used for centuries throughout the Middle East to treat different conditions that we now know to be caused by viral infection[157]. A clinical study from Egypt demonstrated that taking black cumin seed oil reduced the viral load of people with chronic hepatitis C infection[158].  Thymoquinone (TQ), the active ingredient in black cumin seed, protects poultry from avian influenza by direct anti-viral and immune stimulating effects that are synergistically enhanced when TQ is combined with curcumin.[159]  TQ causes human blood cells that carry the Epstein Barr virus (EBV) to self-destruct[160], limiting EBV infection. A laboratory model of acute kidney failure caused by severe infection, found TQ to significantly reduce inflammation and protect the kidneys from failing.[161] The researchers believe the damage prevented by TQ is the same damage that occurs in the kidneys of people with covid-19.

Exciting new research has shed light on a unique mechanism by which TQ may modify responses to viral infection. Many viruses, including corona viruses and influenza, depend upon the activity of a human enzyme called TMPRSS2 for entering human cells. [162] The level of TMPRSS2 determines the ease of viral entry. A human protein called interleukin 13 (IL-13) increases the expression of TMPRSS2 in the respiratory system[163]. TQ suppresses the secretion of IL-13 [164]. So does luteolin, another component of TLC[165].

Higher levels of IL-13 increase susceptibility of human respiratory cells to viral infection [166]and increase severity of viral infection in children[167].  A study from the University of Virginia found that higher levels of IL-13 in blood predict the need for mechanical ventilation in patients hospitalized with covid-19.[168]  Australian researchers have recommended inhibition of IL-13 as a way to reduce severity of many types of viral respiratory infection.[169]Thymoquinone and luteolin can help support that strategy.

ANGIOTENSIN 1-7 AND COVID-19

Covid-19 is associated with inflammatory, autoimmune, cardiovascular, and neurologic complications, which include pulmonary vasoconstriction[170], myocardial injury[171], arterial and venous thrombosis[172], stroke[173], vasculitis[174] [175], and a variety of autoimmune and auto-inflammatory syndromes[176] [177] [178] [179] [180]. A distinct pattern of immune disturbances has been described in patients recovering from covid-19, characterized by increase in activated monocytes and deficit of T lymphocytes. [181]. As global experience with covid-19 increases, it has become clear that many individuals who recover from covid-19 have residual or relapsing health problems involving multiple organ systems and that some of these may be immune mediated. [182]

Several research teams have attributed the pleiotrophic manifestations of covid-19 to a virally-induced deficit in the activity of the ACE-2 signaling cascade, a counter-regulatory component of the renin-angiotensin system  (RAS). [183] [184] [185] [186] SARS-CoV-2, the virus that causes covid-19, enters cells by attaching to the transmembrane protein, angiotensin converting enzyme 2 (ACE-2), a carboxypeptidase that cleaves angiotensin II, yielding the heptapeptide angiotensin 1-7. The binding of SARS-CoV-2 to ACE-2 interferes with the enzymatic activity of ACE-2, allowing an increase in angiotensin II and a decrease in angiotensin 1-7.

The actions of angiotensin II and angiotensin 1-7 are opposite. Angiotensin II is a vasoconstrictor that promotes inflammation, fibrosis and thrombosis. A study from China found direct correlation between the level of angiotensin II in blood and both viral load and severity of illness among patients hospitalized with covid-19.[187]  Angiotensin 1-7, in contrast, is a vasodilator that is anti-inflammatory, anti-thrombotic, anti-fibrotic, cardio- reno- and neuroprotective. It achieves these affects by binding to a G-protein-coupled receptor called the Mas-receptor[188] [189] [190] [191] [192] [193] [194].

Angiotensin 1–7 has been studied for its anti-inflammatory properties in several disorders, especially obesity and diabetes, which are significant risk factors for poor outcome of covid-19. In laboratory animals, administration of angiotensin 1-7 protects against the inflammation and hepatic dysfunction induced by obesity, at the same time inhibiting activity of the cytokines TNF-alpha  and Interleukin-6[195], both of which are major factors in the cytokine storm associated with covid-19 infection. Angiotensin 1-7 also reverses vascular inflammation induced by angiotensin II through inhibition of macrophage/ monocyte activation[196]. When administered by injection at supra-physiologic doses for 28 days, angiotensin 1-7 showed no measurable toxicity in dogs or rats.[197]

Enhancement of angiotensin 1-7/Mas receptor signaling is therefore a promising strategy for reducing disease burden and post-infectious morbidity in covid-19. Clinical trials are in progress or have been proposed for the treatment of hospitalized patients with covid-19 using ACE-2 secreting stem cells[198], recombinant human ACE-2[199], or parenterally-administered analogues of angiotensin 1-7[200].

Angiotensin 1-7 is available for pharmacologic use, although its short plasma half-life is considered an impediment[201].  In a study of mice exposed to whole body radiation, however, subcutaneous injection of angiotensin 1-7 once daily, beginning hours or even days after radiation, significantly reduced pulmonary damage[202], so the short half-life may not prevent significant physiologic effects.

Human clinical trials of angiotensin 1-7 administration have shown no toxicity or adverse reactions:

  1. In women receiving chemotherapy for breast cancer, a daily dose of angiotensin 1-7 (100 mcg/kg) reduced thrombocytopenia, anemia and high grade lymphopenia better than the drug filagastrin. No adverse effects were reported[203].
  2. At 100 mcg/kg/day, angiotensin 1-7 injection attenuated the thrombocytopenia and neutropenia induced by chemotherapy among women with ovarian cancer.[204]
  3. In a double-blind, placebo-controlled clinical trial, an orally absorbed preparation of angiotensin 1-7 was shown to have significant anti-inflammatory activity, reducing both pain and circulating levels of the cytokine TNF-alpha after provocation by excessive eccentric muscular exercise[205]. The preparation used was an inclusion compound of angiotensin 1-7 and hydroxypropyl β-cyclodextrin that had shown significant pharmacologic effects on oral administration in several animal models of disease.

 

[1] https://www.harvardmagazine.com/2020/05/r-nought

[2] .What the cruise-ship outbreaks reveal about COVID-19. Mallapaty S.  Nature. 2020 Apr;580(7801):18. doi: 10.1038/d41586-020-00885-w

[3] https://www.nature.com/articles/s41591-020-0869-5

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. 2020 May;26(5):672-675. doi: 10.1038/s41591-020-0869-5. Epub 2020 Apr 15.

[4] 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.

https://ajp.amjpathol.org/action/showPdf?pii=S0002-9440%2820%2930328-X

[5] 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.

[6] https://www.npr.org/sections/health-shots/2020/10/20/925441975/studies-point-to-big-drop-in-covid-19-death-rates

[7] https://www.medrxiv.org/content/10.1101/2020.10.20.20215863v1.full.pdf

[8] https://www.sciencealert.com/coronavirus-mutations-what-we-ve-learned-so-far?utm_campaign=AppleNews&utm_medium=referral&utm_source=AppleNews

[9]https://www.medscape.com/viewarticle/935758?src=mkm_covid_update_200814_mscpedit_&uac=372244BT&impID=2507481&faf=1

[10] https://www.cdc.gov/mmwr/volumes/69/wr/mm6944e1.htm

[11] 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

[12] https://jamanetwork.com/journals/jama/fullarticle/2763852

Turbulent Gas Clouds and Respiratory Pathogen EmissionsPotential Implications for Reducing Transmission of COVID-19. Lydia Bourouiba, PhD1 JAMA. 2020;323(18):1837-1838. doi:10.1001/jama.2020.4756

[13]  https://www.pnas.org/content/early/2020/05/12/2006874117.long

The airborne lifetime of 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.

[14] 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.i8.1391 PMCID: PMC7190947. PMID: 32368532

[15] 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)

[16] https://www.bloomberg.com/news/articles/2020-07-23/virus-can-jump-26-feet-at-cold-meat-plants-filled-with-stale-air

[17] https://scienmag.com/aerosol-microdroplets-inefficient-carriers-of-covid-19-virus/

[18] https://bgr.com/2020/11/27/coronavirus-transmission-mayo-clinic-face-mask-study/

[19] https://www.webmd.com/lung/news/20200708/air-conditioning-may-be-spreading-covid?ecd=wnl_spr_070820&ctr=wnl-spr-070820_nsl-LeadModule_cta&mb=Fj%40IeljkIwD8MMMwWGmG2a6Btkq86oGPjyPO8eteE2Y%3d

[20] 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/jiaa274https://watermark.silverchair.com/jiaa274.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAApMwggKPBgkqhkiG9w0BBwagggKAMIICfAIBADCCAnUGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQM1FfP53zlRhuIsAMcAgEQgIICRpFzcKUx4pIu3UcXTFp9mK1iwqw5rMpY-dNB8qQNY7DOTy67I1vkWP7cooK-8AYKDPSm9nSljKlQjqMroX25rI2dV3Y3EwdITr_mpc9gk5LSDQk8HWrkBJjZo7ISBAod79Dfk-OhXpOSuq-akbVTptuGhxJJYqgvG213bMYvIDqUdPLmwoHxxmSW7S19LfF4EP6I8RlqT9Ss23neMIEgMTc0v8kyMdquf2KrDI4dSneZ8CaPTgSoBXw4Xx8oRyuH2905a-VWEXV7GVwBdzhHfd0-8_ecoXvpEVkdm5JfXAvtIWDGgJH2jNbcoyQDlJlaAMOQlrRPfy-k7gQQyTqTruvpWjX1l3nm2H3ZR3qVJCCPlwbILKn1BWb_8e_4gPOu-e-NYFdq0z7Hx86KGAF04q230SHjVkXda1qN29M0ABLYl4N-xe7nHATGZZsI397jCNI25XwSQxsAKUTzXUUJU0VQkjRLBBNm7NOdgOHlrsVV-tpoofunbjZWCrWCfbCgEORvGk2QC_OimQPwkmZKsWRFM35juNrfuf-wj2IJIizJp2Rns7oztG5svwshw4-eRr8b1ShZXt1E1sVZfET3JVB4nUfnIW0eh6hlrZQSitlLfNDf6WsXgqV4X1OZVYQ7d6dEQ7-l3q3z2CaNoxVNsJKLCFRbeiIwlmKFYkWJvtgdSGblEso0LVG6-ifyflmKbIvDbnbRSNsrHtHl73KAFdWbFYl37S8NSLhVKoB9b_CCKe1IwyLnwoQGoi_xoUIUnSwXws56zA

[21] https://www.forbes.com/sites/karenrobinsonjacobs/2020/07/25/how-20-lifeguards-got-coronavirus-experts-say-gatherings-among-family-friends-spread-the-virus/#76a6b6b53963

[22] 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

https://www.cell.com/cell/pdf/S0092-8674(20)30675-9.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420306759%3Fshowall%3Dtrue

[23] https://scienmag.com/how-sars-cov-2-reaches-the-brain/

[24] https://www.medscape.com/viewarticle/940252?src=mkm_covid_update_201103_MSCPEDIT&uac=372244BT&impID=2655209&faf=1

[25] https://www.vox.com/future-perfect/21299527/masks-coronavirus-covid-19-studies-research-evidence

[26] https://www.theladders.com/career-advice/researchers-just-made-a-startling-discovery-about-this-nasal-spray-and-covid-19-treatment

[27] 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

https://www.biorxiv.org/content/10.1101/2020.06.08.140236v1.full

[28] https://www.inquisitr.com/6219367/coronavirus-nasal-spray/

[29] https://www.forbes.com/sites/williamhaseltine/2020/11/10/this-nasal-spray-could-be-the-breakthrough-we-need-to-end-covid-19/?sh=3a7fed394132

[30] https://scienmag.com/marinomed-to-trial-carragelose-for-covid19-prevention-in-frontline-healthcare-staff/

[31] 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. 2020 Mar 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

[32] https://academic.oup.com/cid/article/doi/10.1093/cid/ciaa1057/5877944

[33] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095230/ 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

[34] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048229/

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

[35] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158584/

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

[36] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172436/

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

[37] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095102/

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

[38] https://wwwnc.cdc.gov/eid/article/26/8/20-0681_article?deliveryName=USCDC_333-DM28664

[39] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7130008/

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

[40] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095230/

COVID-19: faecal-oral transmission? Hindson J. Nat Rev Gastroenterol Hepatol. 2020 May;17(5):259. doi: 10.1038/s41575-020-0295-

[41] https://www.ncbi.nlm.nih.gov/pubmed/32418307

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

[42] https://www.businessinsider.com/diamond-princess-coronavirus-outbreak-investigation-food-workers-2020-3

[43] https://www.bloomberg.com/news/articles/2020-07-10/china-points-to-shrimp-as-covid-19-carrier-after-salmon-debacle?utm_campaign=news&utm_medium=bd&utm_source=applenews

[44] https://www.cnn.com/2020/08/13/asia/china-coronavirus-chicken-wings-intl-hnk/index.html

[45]https://www.medscape.com/viewarticle/933347?src=mkm_covid_update_200706_mscpedit_&uac=372244BT&impID=2448946&faf=1

[46] https://theconversation.com/coronavirus-scientists-uncover-why-some-people-lose-their-sense-of-smell-138898

[47] 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

https://pubmed.ncbi.nlm.nih.gov/18598095/

[48] 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

https://pubmed.ncbi.nlm.nih.gov/19887043/

[49] https://www.wsj.com/articles/damaged-sense-of-smell-in-covid-patients-holds-clues-to-how-recovery-might-work-11606140319

[50] https://www.webmd.com/lung/news/20201201/smell-training-might-speed-the-senses-return-after-covid?src=RSS_PUBLIC

[51] Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-2040. doi:10.1182/blood.2020006000

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273827/

[52] 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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080116/

[53] 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

https://journals.physiology.org/doi/abs/10.1152/ajplung.00195.2020?rfr_dat=cr_pub++0www.ncbi.nlm.nih.gov&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org

[54]  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

https://www.ahajournals.org/doi/epub/10.1161/CIRCULATIONAHA.120.047915

[55] 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. 2020 Apr 13. pii: S0889-1591(20)30489-X. doi: 10.1016/j.bbi.2020.04.027.

https://www.bloomberg.com/news/articles/2020-05-12/covid-19-s-health-effects-can-last-long-after-virus-is-gone

https://www.bloomberg.com/news/articles/2020-05-01/-false-dawn-recovery-haunts-virus-survivors-who-fall-sick-again

https://www.nbcnewyork.com/news/coronavirus/coronavirus-after-effects-ny-doctor-develops-heart-disease-after-recovery/2397699/

https://www.medscape.com/viewarticle/929631?nlid=135317_2049&src=WNL_mdplsnews_200501_mscpedit_imed&uac=372244BT&spon=18&impID=2366765&faf=1

https://www.webmd.com/lung/news/20200513/complications-on-the-road-to-recovery-after-covid?ecd=wnl_spr_051420&ctr=wnl-spr-051420_nsl-Bodymodule_Position1&mb=Fj%40IeljkIwD8MMMwWGmG2a6Btkq86oGPjyPO8eteE2Y%3d

[56] https://jamanetwork.com/journals/jama/fullarticle/2768351

[57] 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

https://www.cdc.gov/mmwr/volumes/69/wr/mm6930e1.htm?s_cid=mm6930e1_w

[58] Immune cell profiling of COVID-19 patients 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. 2020 May 4;6:31. doi: 10.1038/s41421-020-0168-9. eCollection 2020. PMID: 32377375

[59] https://www.inverse.com/mind-body/covid-19-when-are-you-most-infectious

[60] 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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184421/

[61] https://www.medscape.com/viewarticle/939374?src=wnl_edit_tpal&uac=372244BT&impID=2631824&faf=1

[62] https://www.ncbi.nlm.nih.gov/pubmed/32196933

[63] https://www.medscape.com/viewarticle/936018?src=wnl_tp10j_201015_mscpedit&uac=372244BT&impID=2610621&faf=1

[64] https://www.medscape.com/viewarticle/939022?src=WNL_clfoc_201116_MSCPEDIT_TEMP2&uac=372244BT&impID=2673826&faf=1

[65]  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

https://pubmed.ncbi.nlm.nih.gov/32584322/

[66] https://www.nature.com/articles/s41586-020-2456-9_reference.pdf

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

Described in Medscape: https://www.medscape.com/viewarticle/932715?src=WNL_trdalrt_200626_MSCPEDIT&uac=372244BT&impID=2435677&faf=1

[67] 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

https://www.medrxiv.org/content/10.1101/2020.07.09.20148429v1.full.pdf

[68] https://scienmag.com/new-longitudinal-study-documents-antibody-responses-to-covid-19-5-months-after-symptom-onset/

[69] https://www.medrxiv.org/content/10.1101/2020.12.10.20247205v3

[70] https://science.sciencemag.org/content/370/6515/eabd4585

[71]  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

https://www.medrxiv.org/content/10.1101/2020.06.21.20132449v1.full.pdf

[72] 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

https://www.biorxiv.org/content/10.1101/2020.06.29.174888v1.full.pdf

[73] 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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108125/

[74] https://scienmag.com/exposure-to-common-cold-coronaviruses-can-teach-the-immune-system-to-recognize-sars-cov-2/

[75] https://www.nature.com/articles/s41467-020-17496-8

[76] 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 Online13 Jul 2020. DOI: 10.1126/science.abc6027

https://science.sciencemag.org/content/early/2020/07/10/science.abc6027

[77] 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

https://www.biorxiv.org/content/10.1101/2020.03.07.982264v4

[78] https://www.cell.com/action/showPdf?pii=S0092-8674%2820%2930489-X

[79]  CellPress Volume 27, Issue 6, 10 June 2020, Pages 883-890.e2.Heightened Innate Immune Responses in the Respiratory Tract of COVID-19 Patients ZhuoZhou1214LiliRen2314LiZhang414JiaxinZhong4514YanXiao214ZhilongJia6LiGuo2JingYang45ChunWang45ShuaiJiang4DonghongYang7GuoliangZhang8HongruLi9FuhuiChen10YuXu7MingweiChen11ZhanchengGao7JianYang2JianweiWang2315

https://www.sciencedirect.com/science/article/pii/S1931312820302444

https://reader.elsevier.com/reader/sd/pii/S1931312820302444?token=F00A396A641D1FEFE710C96F6CB819DAE22FB52F684432804DFEDE07DD8BDA57C2016AF60BEC72047108B6E459EA9A3D

[80] https://www.scienceboard.net/index.aspx?sec=sup&sub=imm&pag=dis&ItemID=1167

[81] 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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273815/

[82] 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

https://pubmed.ncbi.nlm.nih.gov/32551464/

[83] IL-13 Predicts the Need for Mechanical Ventilation in COVID-19 Patients. Alexandra N Donlan, Mary Young, William A Petri Jr., Mayuresh Abhyankar. medRxiv 2020.06.18.20134353; doi: https://doi.org/10.1101/2020.06.18.20134353

https://www.medrxiv.org/content/10.1101/2020.06.18.20134353v1.full.pdf

[84] 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

https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6929a1-H.pdf

[85] https://www.businessinsider.com/coronavirus-compared-seasonal-flu-in-the-us-death-rates-2020-3

[86] Ing AJ, Cocks C, Green JP COVID-19: in the footsteps of Ernest Shackleton. Thorax 2020;75:693-694.

https://thorax.bmj.com/content/thoraxjnl/early/2020/05/27/thoraxjnl-2020-215091.full.pdf

[87] https://www.cdc.gov/mmwr/volumes/69/wr/mm6919e6.htm

[88] https://theconversation.com/to-understand-the-danger-of-covid-19-outbreaks-in-meatpacking-plants-look-at-the-industrys-history-137367

[89] https://www.biospace.com/article/multiple-studies-suggest-covid-19-mortality-rate-may-be-lower-than-expected-/

[90] https://www.grassrootshealth.net/wp-content/uploads/2020/04/Alipio-Vit-D-COVID-Severity-Preprint-04-22-2020.pdf?utm_source=With+PDF+-+Vit+D+COVID+Severity+-+News+Thurs+4%2F23+%28Sent+Wed%29&utm_campaign=Newsletter&utm_medium=email

[91] Evidence Supports a Causal Role for Vitamin D Status in COVID-19 Outcomes.Gareth Davies, Attila R Garami, Joanna C Byers

medRxiv 2020.05.01.20087965; doi: https://doi.org/10.1101/2020.05.01.20087965

https://www.medrxiv.org/content/10.1101/2020.05.01.20087965v3.full.pdf

[92] https://www.nature.com/articles/d41586-020-02948-4

[93]  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

[94] 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

[95] 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

[96] 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

[97] https://unitedwithisrael.org/revolutionary-israeli-corona-blocker-nasal-spray-stops-covid-spread/

[98] Vidricaire G, Denault JB, Leduc R (1993) Characterization of a secreted form of human furin endoprotease. Biochem Biophys Res Commun 195: 1011 – 1018

[99] 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

[100] Wu C, Yang Y, Liu Y, Zhang P, Wang Y, Wang Q, Xu Y, Li M, Zheng M, Chen Let al (2020b) Furin, a potential therapeutic target for COVID-19. chinaRxiv

https://doi.org/10.12074/202002.00062

[101] https://www.news-medical.net/news/20201123/Compounds-in-traditional-Chinese-medicine-herbs-may-inhibit-SARS-CoV-2-infection.aspx

[102] https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3682517

[103] https://pubs.acs.org/doi/pdf/10.1021/acs.jafc.0c05064

[104] https://pubmed.ncbi.nlm.nih.gov/20406213/

[105] Kimura H, Francisco D, Conway M, et al. Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells. J Allergy Clin Immunol. 2020;146(1):80-88.e8. doi:10.1016/j.jaci.2020.05.004

https://pubmed.ncbi.nlm.nih.gov/32422146/

[106] https://www.jacionline.org/action/showPdf?pii=S0091-6749%2820%2931136-2

[107] https://www.nature.com/articles/s41598-020-77791-8

[108] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502909/

[109] Mahmudpour M, Roozbeh J, Keshavarz M, Farrokhi S, Nabipour I. COVID-19 cytokine storm: The anger of inflammation. Cytokine. 2020;133:155151. doi:10.1016/j.cyto.2020.155151

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260598/

[110] https://juniperpublishers.com/ijoprs/pdf/IJOPRS.MS.ID.555641.pdf

[111] https://www.medscape.com/viewarticle/938759?nlid=137761_3243&src=WNL_mdplsfeat_201013_mscpedit_imed&uac=372244BT&spon=18&impID=2618040&faf=1

[112] https://www.cnn.com/2020/08/03/health/fda-hand-sanitizers-list-expands-trnd/index.html

[113] https://www.foxnews.com/health/new-toxin-found-some-hand-sanitizers-fda

[114] A review of 34 studies found that simple masks, even homemade ones, have a significant protective effect on viral spread through communities.

https://www.washingtonpost.com/outlook/2020/03/28/masks-all-coronavirus/.

[115] 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

DOI: 10.1126/sciadv.abd3083

https://advances.sciencemag.org/content/early/2020/08/07/sciadv.abd3083

[116] https://www.webmd.com/lung/news/20200807/simple-test-shows-which-face-masks-are-best?src=RSS_PUBLIC

[117] https://www.medscape.com/viewarticle/938970?src=mkm_covid_update_201012_mscpedit_&uac=372244BT&impID=2616440&faf=1

[118] https://www.businesswire.com/news/home/20200709005991/en/Laboratory-Studies-Confirm-BETADINE%C2%AE-Antiseptic-Products%E2%80%99-Effectiveness

[119] 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

[120] Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity. Martino et al. https://www.biorxiv.org/content/10.1101/2020.08.17.238444v1.full.pdf

[121] 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

[122] 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

[123] 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

[124]  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

[125] https://unitedwithisrael.org/revolutionary-israeli-corona-blocker-nasal-spray-stops-covid-spread/

[126] Yan H, Ma L, Wang H, et al. Luteolin decreases the yield of influenza A virus in vitro by interfering with the coat protein I complex expression. J Nat Med. 2019;73(3):487-496. doi:10.1007/s11418-019-01287-7

https://pubmed.ncbi.nlm.nih.gov/30758716/

[127] Bai L, Nong Y, Shi Y, et al. Luteolin Inhibits Hepatitis B Virus Replication through Extracellular Signal-Regulated Kinase-Mediated Down-Regulation of Hepatocyte Nuclear Factor 4α Expression. Mol Pharm. 2016;13(2):568-577. doi:10.1021/acs.molpharmaceut.5b00789

https://pubmed.ncbi.nlm.nih.gov/26656210/

[128] Yi L, Li Z, Yuan K, et al. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol. 2004;78(20):11334-11339. doi:10.1128/JVI.78.20.11334-11339.2004

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC521800/

[129] Wu CC, Fang CY, Hsu HY, et al. Luteolin inhibits Epstein-Barr virus lytic reactivation by repressing the promoter activities of immediate-early genes. Antiviral Res. 2016;132:99-110. doi:10.1016/j.antiviral.2016.05.007

https://pubmed.ncbi.nlm.nih.gov/27185626/

[130] Murali KS, Sivasubramanian S, Vincent S, et al. Anti-chikungunya activity of luteolin and apigenin rich fraction from Cynodon dactylon. Asian Pac J Trop Med. 2015;8(5):352-358. doi:10.1016/S1995-7645(14)60343-6

https://www.sciencedirect.com/science/article/pii/S1995764514603436?via%3Dihub

[131] Fan W, Qian S, Qian P, Li X. Antiviral activity of luteolin against Japanese encephalitis virus. Virus Res. 2016;220:112-116. doi:10.1016/j.virusres.2016.04.021

https://pubmed.ncbi.nlm.nih.gov/27126774/

[132] Peng M, Watanabe S, Chan KWK, et al. Luteolin restricts dengue virus replication through inhibition of the proprotein convertase furin. Antiviral Res. 2017;143:176-185. doi:10.1016/j.antiviral.2017.03.026

https://pubmed.ncbi.nlm.nih.gov/28389141/

[133] The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E (2020). Antiviral Res 176:104742

[134] A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin. 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) Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2020.1754293

[135] Ryu YB, Jeong HJ, Kim JH, et al. Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition. Bioorg Med Chem. 2010;18(22):7940-7947. doi:10.1016/j.bmc.2010.09.035

https://pubmed.ncbi.nlm.nih.gov/20934345/

[136] Liu CW, Lin HW, Yang DJ, et al. Luteolin inhibits viral-induced inflammatory response in RAW264.7 cells via suppression of STAT1/3 dependent NF-κB and activation of HO-1. Free Radic Biol Med. 2016;95:180-189. doi:10.1016/j.freeradbiomed.2016.03.019

https://pubmed.ncbi.nlm.nih.gov/27016074/

[137] Zhang XX, Wu QF, Yan YL, Zhang FL. Inhibitory effects and related molecular mechanisms of total flavonoids in Mosla chinensis Maxim against H1N1 influenza virus. Inflamm Res. 2018;67(2):179-189. doi:10.1007/s00011-017-1109-4

https://pubmed.ncbi.nlm.nih.gov/29177921/

[138] Theoharides TC. COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin. Biofactors. 2020;46(3):306-308. doi:10.1002/biof.1633

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267424/

[139] Huang YF, Bai C, He F, Xie Y, Zhou H. Review on the potential action mechanisms of Chinese medicines in treating Coronavirus Disease 2019 (COVID-19). Pharmacol Res. 2020;158:104939. doi:10.1016/j.phrs.2020.104939

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239792/

[140] Hirano T, Higa S, Arimitsu J, et al. Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils. Int Arch Allergy Immunol. 2004;134(2):135-140. doi:10.1159/000078498

https://pubmed.ncbi.nlm.nih.gov/15153793/

[141] IL-13 Predicts the Need for Mechanical Ventilation in COVID-19 Patients. Alexandra N Donlan, Mary Young, William A Petri Jr., Mayuresh Abhyankar. medRxiv 2020.06.18.20134353; doi: https://doi.org/10.1101/2020.06.18.20134353  https://www.medrxiv.org/content/10.1101/2020.06.18.20134353v1.full.pdf

[142] Zhang L, Wang X, Zhang L, Virgous C, Si H. Combination of curcumin and luteolin synergistically inhibits TNF-α-induced vascular inflammation in human vascular cells and mice. J Nutr Biochem. 2019;73:108222. doi:10.1016/j.jnutbio.2019.108222

https://pubmed.ncbi.nlm.nih.gov/31665675/

[143] Xu Y, Liu L. Curcumin alleviates macrophage activation and lung inflammation induced by influenza virus infection through inhibiting the NF-κB signaling pathway. Influenza Other Respir Viruses. 2017;11(5):457-463. doi:10.1111/irv.12459

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596526/

[144] Han S, Xu J, Guo X, Huang M. Curcumin ameliorates severe influenza pneumonia via attenuating lung injury and regulating macrophage cytokines production. Clin Exp Pharmacol Physiol. 2018;45(1):84-93. doi:10.1111/1440-1681.12848

https://pubmed.ncbi.nlm.nih.gov/28853207/

[145] Avasarala S, Zhang F, Liu G, Wang R, London SD, London L. Curcumin modulates the inflammatory response and inhibits subsequent fibrosis in a mouse model of viral-induced acute respiratory distress syndrome [published correction appears in PLoS One. 2015;10(8):e0134982]. PLoS One. 2013;8(2):e57285. doi:10.1371/journal.pone.0057285

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577717/

[146] Song Y, Ge W, Cai H, Zhang H. Curcumin protects mice from coxsackievirus B3-induced myocarditis by inhibiting the phosphatidylinositol 3 kinase/Akt/nuclear factor-κB pathway. J Cardiovasc Pharmacol Ther. 2013;18(6):560-569. doi:10.1177/1074248413503044

https://pubmed.ncbi.nlm.nih.gov/24057864/

[147] Vitali D, Bagri P, Wessels JM, et al. Curcumin Can Decrease Tissue Inflammation and the Severity of HSV-2 Infection in the Female Reproductive Mucosa. Int J Mol Sci. 2020;21(1):337. Published 2020 Jan 4. doi:10.3390/ijms21010337

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982333/

[148] Ferreira VH, Nazli A, Dizzell SE, Mueller K, Kaushic C. The anti-inflammatory activity of curcumin protects the genital mucosal epithelial barrier from disruption and blocks replication of HIV-1 and HSV-2. PLoS One. 2015;10(4):e0124903. Published 2015 Apr 9. doi:10.1371/journal.pone.0124903

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391950/

[149] Zhang L, Wang X, Zhang L, Virgous C, Si H. Combination of curcumin and luteolin synergistically inhibits TNF-α-induced vascular inflammation in human vascular cells and mice. J Nutr Biochem. 2019;73:108222. doi:10.1016/j.jnutbio.2019.10822

https://pubmed.ncbi.nlm.nih.gov/31665675/

[150] Al Fayi M, Otifi H, Alshyarba M, Dera AA, Rajagopalan P. Thymoquinone and curcumin combination protects cisplatin-induced kidney injury, nephrotoxicity by attenuating NFκB, KIM-1 and ameliorating Nrf2/HO-1 signalling [published online ahead of print, 2020 Feb 5]. J Drug Target. 2020;1-10. doi:10.1080/1061186X.2020.1722136

https://pubmed.ncbi.nlm.nih.gov/31983246/

[151] Amin F, Gilani AH, Mehmood MH, Siddiqui BS, Khatoon N. Coadministration of black seeds and turmeric shows enhanced efficacy in preventing metabolic syndrome in fructose-fed rats. J Cardiovasc Pharmacol. 2015;65(2):176-183. doi:10.1097/FJC.0000000000000179

https://pubmed.ncbi.nlm.nih.gov/25384193/

[152] Umar S, Shah MAA, Munir MT, et al. Synergistic effects of thymoquinone and curcumin on immune response and anti-viral activity against avian influenza virus (H9N2) in turkeys. Poult Sci. 2016;95(7):1513-1520. doi:10.3382/ps/pew069

https://pubmed.ncbi.nlm.nih.gov/26944958/

[153] Zahedipour F, Hosseini SA, Sathyapalan T, et al. Potential effects of curcumin in the treatment of COVID-19 infection [published online ahead of print, 2020 May 19]. Phytother Res. 2020;10.1002/ptr.6738. doi:10.1002/ptr.6738

https://onlinelibrary.wiley.com/doi/full/10.1002/ptr.6738

[154] Rocha FAC, de Assis MR. Curcumin as a potential treatment for COVID-19 [published online ahead of print, 2020 May 22]. Phytother Res. 2020;10.1002/ptr.6745. doi:10.1002/ptr.6745

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280567/pdf/PTR-9999-na.pdf

[155] Hooper PL. COVID-19 and heme oxygenase: novel insight into the disease and potential therapies [published online ahead of print, 2020 Jun 4] [published correction appears in Cell Stress Chaperones. 2020 Jun 29;:]. Cell Stress Chaperones. 2020;1-4. doi:10.1007/s12192-020-01126-9

https://link.springer.com/article/10.1007/s12192-020-01126-9

[156] Maurya VK, Kumar S, Prasad AK, Bhatt MLB, Saxena SK. Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor. Virusdisease. 2020;31(2):179-193. doi:10.1007/s13337-020-00598-8

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245990/

[157] Black cumin (Nigella sativa) and its constituent (thymoquinone): a review on antimicrobial effects. Forouzanfar F, Bazzaz BS, Hosseinzadeh H. Iran J Basic Med Sci. 2014 Dec;17(12):929-38. PMID: 25859296

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387228/

[158] Barakat EM, El Wakeel LM, Hagag RS. Effects of Nigella sativa on outcome of hepatitis C in Egypt. World J Gastroenterol. 2013;19:2529–2536

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646144/

[159] Synergistic effects of thymoquinone and curcumin on immune response and anti-viral activity against avian influenza virus (H9N2) in turkeys.  Umar S, Shah MAA, Munir MT, Yaqoob M, Fiaz M, Anjum S, Kaboudi K, Bouzouaia M, Younus M, Nisa Q, Iqbal M, Umar W. Poult Sci. 2016 Jul 1;95(7):1513-1520. doi: 10.3382/ps/pew069. Epub 2016 Mar 4. PMID: 26944958

https://pubmed.ncbi.nlm.nih.gov/26944958/

[160] Thymoquinone efficiently inhibits the survival of EBV-infected B cells and alters EBV gene expression.

Zihlif MA, Mahmoud IS, Ghanim MT, Zreikat MS, Alrabadi N, Imraish A, Odeh F, Abbas MA, Ismail SI. Integr Cancer Ther. 2013 May;12(3):257-63. doi: 10.1177/1534735412458827. Epub 2012 Oct 21. PMID: 23089554

https://pubmed.ncbi.nlm.nih.gov/23089554/

[161]Guo LP, Liu SX, Yang Q, et al. Effect of Thymoquinone on Acute Kidney Injury Induced by Sepsis in BALB/c Mice. Biomed Res Int. 2020;2020:1594726. Published 2020 Jun 16. doi:10.1155/2020/1594726 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315249/

[162] TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Shen LW, Mao HJ, Wu YL, Tanaka Y, Zhang W. Biochimie. 2017 Nov;142:1-10. doi: 10.1016/j.biochi.2017.07.016.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116903/

[163]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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239056/

[164] El Gazzar MA. Thymoquinone suppressses in vitro production of IL-5 and IL-13 by mast cells in response to lipopolysaccharide stimulation. Inflamm Res. 2007;56(8):345-351. doi:10.1007/s00011-007-7051-0

https://pubmed.ncbi.nlm.nih.gov/17687519/

[165] Hirano T, Higa S, Arimitsu J, et al. Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils. Int Arch Allergy Immunol. 2004;134(2):135-140. doi:10.1159/00007849

https://pubmed.ncbi.nlm.nih.gov/15153793/

[166] Lachowicz-Scroggins ME, Boushey HA, Finkbeiner WE, Widdicombe JH. Interleukin-13-induced mucous metaplasia increases susceptibility of human airway epithelium to rhinovirus infection. Am J Respir Cell Mol Biol. 2010;43(6):652-661. doi:10.1165/rcmb.2009-0244OC

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993086/

[167] Caballero MT, Hijano DR, Acosta PL, et al. Interleukin-13 associates with life-threatening rhinovirus infections in infants and young children. Pediatr Pulmonol. 2018;53(6):787-795. doi:10.1002/ppul.23998

https://pubmed.ncbi.nlm.nih.gov/29665312/

[168] IL-13 Predicts the Need for Mechanical Ventilation in COVID-19 PatientsAlexandra N Donlan, Mary Young, William A Petri Jr., Mayuresh Abhyankar. medRxiv 2020.06.18.20134353; doi: https://doi.org/10.1101/2020.06.18.20134353

https://www.medrxiv.org/content/10.1101/2020.06.18.20134353v1.full.pdf

[169] Donovan C, Bourke JE, Vlahos R. Targeting the IL-33/IL-13 Axis for Respiratory Viral Infections. Trends Pharmacol Sci. 2016;37(4):252-261. doi:10.1016/j.tips.2016.01.004

https://pubmed.ncbi.nlm.nih.gov/26833119/

[170] Clinical phenotypes of SARS-CoV-2: Implications for clinicians and researchers. Rello J, Storti E, Belliato M, Serrano R. Eur Respir J. 2020 Apr 27. pii: 2001028. doi: 10.1183/13993003.01028-2020

[171] Myocardial injury and COVID-19: Possible mechanisms. Babapoor-Farrokhran S, Gill D, Walker J, Rasekhi RT, Bozorgnia B, Amanullah A. Life Sci. 2020 Apr 28;253:117723. doi: 10.1016/j.lfs.2020.117723

[172] Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study.Wichmann D, Sperhake JP, Lütgehetmann M, Steurer S, Edler C, Heinemann A, Heinrich F, Mushumba H, Kniep I, Schröder AS, Burdelski C, de Heer G, Nierhaus A, Frings D, Pfefferle S, Becker H, Bredereke-Wiedling H, de Weerth A, Paschen HR, Sheikhzadeh-Eggers S, Stang A, Schmiedel S, Bokemeyer C, Addo MM, Aepfelbacher M, Püschel K, Kluge S. Ann Intern Med. 2020 May 6. doi: 10.7326/M20-2003.

[173] COVID-19-Related Stroke. Hess DC, Eldahshan W, Rutkowski E. Transl Stroke Res. 2020 May 7. doi: 10.1007/s12975-020-00818-9.

[174] Symmetric cutaneous vasculitis in COVID-19 pneumonia. Castelnovo L, Capelli F, Tamburello A, Maria Faggioli P, Mazzone A. J Eur Acad Dermatol Venereol. 2020 May 7. doi: 10.1111/jdv.16589.

[175] Chilblains-like lesions in children following suspected Covid-19 infection. Colonna C, Monzani NA, Rocchi A, Gianotti R, Boggio F, Gelmetti C. Pediatr Dermatol. 2020 May 6. doi: 10.1111/pde.14210

[176] Autoimmune hemolytic anemia associated with Covid-19 infection.Lazarian G, Quinquenel A, Bellal M, Siavellis J, Jacquy C, Re D, Merabet F, Mekinian A, Braun T, Damaj G, Delmer A, Cymbalista F. Br J Haematol. 2020 May 6. doi: 10.1111/bjh.16794

[177] Is COVID-19 a proteiform disease inducing also molecular mimicry phenomena? Cappello F. Cell Stress Chaperones. 2020 May;25(3):381-382. doi: 10.1007/s12192-020-01112-1. Epub 2020 Apr 20.

[178] Pathogenic Priming Likely Contributes to Serious and Critical Illness and Mortality in COVID-19 via Autoimmunity.Lyons-Weiler J. J Transl Autoimmun. 2020 Apr 9:100051. doi: 10.1016/j.jtauto.2020.100051.

[179] Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects? Caso F, Costa L, Ruscitti P, Navarini L, Del Puente A, Giacomelli R, Scarpa R. Autoimmun Rev. 2020May;19(5):102524. doi: 10.1016/j.autrev.2020. 102524.  Epub 2020 Mar 24.

[180] Response to “Lupus anticoagulant is frequent in patients with Covid-19”. Tang N. J Thromb Haemost. 2020 May 7. doi: 10.1111/jth.14890

[181] Immune cell profiling of COVID-19 patients 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. 2020 May 4;6:31. doi: 10.1038/s41421-020-0168-9. eCollection 2020. PMID: 32377375

[182] 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. 2020 Apr 13. pii: S0889-1591(20)30489-X. doi: 10.1016/j.bbi.2020.04.027.

https://www.bloomberg.com/news/articles/2020-05-01/-false-dawn-recovery-haunts-virus-survivors-who-fall-sick-again

https://www.nbcnewyork.com/news/coronavirus/coronavirus-after-effects-ny-doctor-develops-heart-disease-after-recovery/2397699/

https://www.medscape.com/viewarticle/929631?nlid=135317_2049&src=WNL_mdplsnews_200501_mscpedit_imed&uac=372244BT&spon=18&impID=2366765&faf=1

[183] The ACE-2 in COVID-19: Foe or Friend? Dalan R, Bornstein SR, El-Armouche A, Rodionov RN, Markov A, Wielockx B, Beuschlein F, Boehm BO. Horm Metab Res. 2020 Apr 27. doi: 10.1055/a-1155-0501

[184]  The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Verdecchia P1, Cavallini C2, Spanevello A3, Angeli F3.  Eur J Intern Med. 2020 Apr 20. pii: S0953-6205(20)30151-5. doi: 10.1016/j.ejim.2020.04.037.

[185] ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel? Xiao L, Sakagami H, Miwa N. Viruses. 2020 Apr 28;12(5). pii: E491. doi: 10.3390/v12050491. PMID: 32354022

[186] COVID-19: A New Virus, but a Familiar Receptor and Cytokine Release Syndrome. Hirano T, Murakami M. Immunity. 2020 Apr 19. pii: S1074-7613(20)30161-8. doi: 10.1016/j.immuni. 2020.04.003. PMID: 32325025

[187] Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, Wang Z, Li J, Li J, Feng C, Zhang Z, Wang L, Peng L, Chen L, Qin Y, Zhao D, Tan S, Yin L, Xu J, Zhou C, Jiang C, Liu L.Sci China Life Sci. 2020 Mar;63(3):364-374. doi: 10.1007/s11427-020-1643-8. Epub 2020 Feb 9. PMID: 32048163

[188] Angiotensin-(1–7). Santos RA (2014) Hypertension 63 (6):1138–1147.

[189] The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7). Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, Campagnole-Santos MJ. Physiol Rev. 2018 Jan 1;98(1):505-553. doi: 10.1152/physrev.00023.2016.

[190] The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Li XC, Zhang J, Zhuo JL. Pharmacol Res. 2017 Nov;125(Pt A):21-38. doi: 10.1016/j.phrs.2017.06.005. Epub 2017 Jun 12

[191] The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research. Rodrigues Prestes TR, Rocha NP, Miranda AS, Teixeira AL, Simoes-E-Silva AC. Curr Drug Targets. 2017;18(11):1301-1313. doi: 10.2174/1389450117666160727142401.

[192] ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis. Simões E Silva AC, Teixeira MM. Pharmacol Res. 2016 May;107:154-162. doi: 10.1016/j.phrs.2016.03.018. Epub 2016 Mar 17.

[193] Brain angiotensin-(1-7)/Mas axis: A new target to reduce the cardiovascular risk to emotional stress. Fontes MA, Martins Lima A, Santos RA. Neuropeptides. 2016 Apr;56:9-17. doi: 10.1016/j.npep.2015.10.003. Epub 2015 Oct 26. PMID: 26584971

[194] The angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis: a potential target for treating thrombotic diseases. Fraga-Silva RA, Da Silva DG, Montecucco F, Mach F, Stergiopulos N, da Silva RF, Santos RA. Thromb Haemost. 2012 Dec;108(6):1089-96. doi: 10.1160/TH12-06-0396. Epub 2012 Oct 23. PMID: 23093373

[195]  Santos SH, Andrade JM, Fernandes LR, Sinisterra RD, Sousa FB, Feltenberger JD, et al. Oral angiotensin-(1–7) prevented obesity and hepatic inflammation by inhibitionof resist in/TLR4/MAPK/NF-kappaB in rats fed with high-fat diet. Peptides 2013; 46:47–52.

[196] Souza LL, Costa-Neto CM. Angiotensin-(1–7) decreases LPS-induced inflammatory

response in macrophages. J Cell Physiol 2012;227:2117–22.

[197] Toxicological and toxicokinetic analysis of angiotensin (1-7) in two species.Mordwinkin NM, Russell JR, Burke AS, Dizerega GS, Louie SG, Rodgers KE. J Pharm Sci. 2012 Jan;101(1):373-80. doi: 10.1002/jps.22730. Epub 2011 Aug 19. PMID: 21858825

[198] Transplantation of ACE2 Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia.Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, Shan G, Meng F, Du D, Wang S, Fan J, Wang W, Deng L, Shi H, Li H, Hu Z, Zhang F, Gao J, Liu H, Li X, Zhao Y, Yin K, He X, Gao Z, Wang Y, Yang B, Jin R, Stambler I, Lim LW, Su H, Moskalev A, Cano A, Chakrabarti S, Min KJ, Ellison-Hughes G, Caruso C, Jin K, Zhao RC. Aging Dis. 2020 Mar 9;11(2):216-228. doi: 10.14336/AD.2020.0228. eCollection 2020 Apr.PMID: 32257537

[199] Blockade of SARS-CoV-2 infection by recombinant soluble ACE2. Alhenc-Gelas F, Drueke TB. Kidney Int. 2020 Apr 14. pii: S0085-2538(20)30401-4. doi: 10.1016/j.kint.2020.04.009. PMID: 32354636

[200] Personal communications: Meredith Hay (Department of Physiology, University of Arizona) and Kathleen Rodgers (Department of Pharmacology, University of Arizona)

[201] Angiotensin-(1-7): pharmacological properties and pharmacotherapeutic perspectives.Iusuf D, Henning RH, van Gilst WH, Roks AJ. Eur J Pharmacol. 2008 May 13;585(2-3):303-12. doi: 10.1016/j.ejphar.2008.02.090. Epub 2008 Mar 15. Review.PMID: 18417117

[202] Accelerated hematopoietic recovery with angiotensin-(1-7) after total body radiation.Rodgers KE, Espinoza T, Roda N, Meeks CJ, Hill C, Louie SG, Dizerega GS.Int J Radiat Biol. 2012 Jun;88(6):466-76. doi: 10.3109/09553002.2012.676228. Epub 2012 Apr 30. PMID: 22433112

[203] Phase I/II dose escalation study of angiotensin 1-7 [A(1-7)] administered before and after chemotherapy in patients with newly diagnosed breast cancer. Rodgers KE, Oliver J, diZerega GS. Cancer Chemother Pharmacol. 2006 May;57(5):559-68. Epub 2005 Aug 12. PMID: 16096787

[204] Pharmacodynamic stimulation of thrombogenesis by angiotensin (1-7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy. Pham H, Schwartz BM, Delmore JE, Reed E, Cruickshank S, Drummond L, Rodgers KE, Peterson KJ, diZerega GS. Cancer Chemother Pharmacol. 2013 Apr;71(4):965-72. doi: 10.1007/s00280-013-2089-x. Epub 2013 Jan 31. PMID: 23370663

[205] Eccentric Overload Muscle Damage is Attenuated By a Novel Angiotensin- (1-7) Treatment.Becker LK, Totou N, Moura S, Kangussu L, Millán RDS, Campagnole-Santos MJ, Coelho D, Motta-Santos D, Santos RAS. Int J Sports Med. 2018 Oct;39(10):743-748. doi: 10.1055/a-0633-8892. Epub 2018 Jun 25. PMID: 29940668