Do person with strong immune system have less chance of surviving SARS-COV-2 attack?

Do person with strong immune system have less chance of surviving SARS-COV-2 attack?

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In most of the cases dealing with SARS-COV-2 disease, the major mortality cause is due to cytokine storm in response to Corona-virus that also attack healthy organs causing multiple organ failure.

leading to inflammation and fluid buildup in the lungs.(7) Certain kinds of cytokines trigger cell death. When you have many cells doing this at the same time, a lot of tissue can die. In COVID-19, that tissue is mostly in the lung.(5)

Among the many mysteries of Covid-19 is why relatively healthy young people suddenly become critically ill - or die.Many otherwise robust patients were experiencing cytokine storms. One key sign of that was the body's levels of ferritin, a protein in the body that binds to iron. This massive over-reaction, known as a cytokine storm, is believed to be a major reason that a growing number of exceedingly fit people find themselves fighting for their lives.(7)

Assuming healthy people having a strong immune system have greater cytokine storm against SARS-COV-2, isn't coronavirus naturally selecting people with "weaker" immune response?

However an interesting case has been observed within Haemodialytic patient(not-healthy):

HD patients with COVID-19 even displayed more remarkable reduction of serum inflammatory cytokines than other COVID-19 patients. Epidemiological, clinical, and immunological features of a cluster of COVID-19 contracted hemodialysis patients


  4. The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system
  5. Cytokine Storms May Be Fueling Some COVID Deaths
  6. Why Some COVID-19 Patients Crash: The Body's Immune System Might Be To Blame

  7. He ran marathons and was fit. So why did Covid-19 almost kill him?

After recovering from COVID-19, are you immune?

This undated electron microscope image made available by the U.S. National Institutes of Health in February 2020 shows the coronavirus that causes COVID-19. The sample was isolated from a patient in the U.S. (NIAID-RML via AP)

As coronavirus spreads across the globe, a crucial question has emerged: After recovering from an infection, are people immune?

This question is important for understanding who can safely go back to work, as well as for understanding how long the worst impacts of the pandemic are likely to last. Because the virus is so new, the answer isn't fully understood. But so far, scientists say, it looks like SARS-CoV-2 probably induces immunity like other coronaviruses. That means that the human body will probably retain a memory of the virus for at least a few years and should be protected from reinfection, at least in the short-term.

"We do not have any reason to assume that the immune response would be significantly different" from what's seen with other coronaviruses, said Nicolas Vabret, an assistant professor of medicine at the Mount Sinai Icahn School of Medicine who specializes in virology and immunology.

Investigations of SARS-CoV-2 so far have suggested, however, that the immune response to the virus also contributes to the devastating effects of the disease in some people.

Immunology Is Where Intuition Goes to Die

Which is too bad because we really need to understand how the immune system reacts to the coronavirus.

Updated at 10:36 a.m. ET on August 5, 2020.

There’s a joke about immunology, which Jessica Metcalf of Princeton recently told me. An immunologist and a cardiologist are kidnapped. The kidnappers threaten to shoot one of them, but promise to spare whoever has made the greater contribution to humanity. The cardiologist says, “Well, I’ve identified drugs that have saved the lives of millions of people.” Impressed, the kidnappers turn to the immunologist. “What have you done?” they ask. The immunologist says, “The thing is, the immune system is very complicated …” And the cardiologist says, “Just shoot me now.”

The thing is, the immune system is very complicated. Arguably the most complex part of the human body outside the brain, it’s an absurdly intricate network of cells and molecules that protect us from dangerous viruses and other microbes. These components summon, amplify, rile, calm, and transform one another: Picture a thousand Rube Goldberg machines, some of which are aggressively smashing things to pieces. Now imagine that their components are labeled with what looks like a string of highly secure passwords: CD8+, IL-1β, IFN-γ. Immunology confuses even biology professors who aren’t immunologists—hence Metcalf’s joke.

Even the word immunity creates confusion. When immunologists use it, they simply mean that the immune system has responded to a pathogen—for example, by producing antibodies or mustering defensive cells. When everyone else uses the term, they mean (and hope) that they are protected from infection—that they are immune. But, annoyingly, an immune response doesn’t necessarily provide immunity in this colloquial sense. It all depends on how effective, numerous, and durable those antibodies and cells are.

Immunity, then, is usually a matter of degrees, not absolutes. And it lies at the heart of many of the COVID-19 pandemic’s biggest questions. Why do some people become extremely ill and others don’t? Can infected people ever be sickened by the same virus again? How will the pandemic play out over the next months and years? Will vaccination work?

To answer these questions, we must first understand how the immune system reacts to SARS-CoV-2 coronavirus. Which is unfortunate because, you see, the immune system is very complicated.

It works, roughly, like this.

The first of three phases involves detecting a threat, summoning help, and launching the counterattack. It begins as soon as a virus drifts into your airways, and infiltrates the cells that line them.

When cells sense molecules common to pathogens and uncommon to humans, they produce proteins called cytokines. Some act like alarms, summoning and activating a diverse squad of white blood cells that go to town on the intruding viruses—swallowing and digesting them, bombarding them with destructive chemicals, and releasing yet more cytokines. Some also directly prevent viruses from reproducing (and are delightfully called interferons). These aggressive acts lead to inflammation. Redness, heat, swelling, soreness—these are all signs of the immune system working as intended.

This initial set of events is part of what’s called the innate immune system. It’s quick, occurring within minutes of the virus’s entry. It’s ancient, using components that are shared among most animals. It’s generic, acting in much the same way in everyone. And it’s broad, lashing out at anything that seems both nonhuman and dangerous, without much caring about which specific pathogen is afoot. What the innate immune system lacks in precision, it makes up for in speed. Its job is to shut down an infection as soon as possible. Failing that, it buys time for the second phase of the immune response: bringing in the specialists.

Amid all the fighting in your airways, messenger cells grab small fragments of virus and carry these to the lymph nodes, where highly specialized white blood cells—T-cells—are waiting. The T-cells are selective and preprogrammed defenders. Each is built a little differently, and comes ready-made to attack just a few of the zillion pathogens that could possibly exist. For any new virus, you probably have a T-cell somewhere that could theoretically fight it. Your body just has to find and mobilize that cell. Picture the lymph nodes as bars full of grizzled T-cell mercenaries, each of which has just one type of target they’re prepared to fight. The messenger cell bursts in with a grainy photo, showing it to each mercenary in turn, asking: Is this your guy? When a match is found, the relevant merc arms up and clones itself into an entire battalion, which marches off to the airways.

Some T-cells are killers, which blow up the infected respiratory cells in which viruses are hiding. Others are helpers, which boost the rest of the immune system. Among their beneficiaries, these helper T-cells activate the B-cells that produce antibodies—small molecules that can neutralize viruses by gumming up the structures they use to latch on to their hosts. Roughly speaking—and this will be important later—antibodies mop up the viruses that are floating around outside our cells, while T-cells kill the ones that have already worked their way inside. T-cells do demolition antibodies do cleanup.

Both T-cells and antibodies are part of the adaptive immune system. This branch is more precise than the innate branch, but much slower: Finding and activating the right cells can take several days. It’s also long-lasting: Unlike the innate branch of the immune system, the adaptive one has memory.

After the virus is cleared, most of the mobilized T-cell and B-cell forces stand down and die off. But a small fraction remain on retainer—veterans of the COVID-19 war of 2020, bunkered within your organs and patrolling your bloodstream. This is the third and final phase of the immune response: Keep a few of the specialists on tap. If the same virus attacks again, these “memory cells” can spring into action and launch the adaptive branch of the immune system without the usual days-long delay. Memory is the basis of immunity as we colloquially know it—a lasting defense against whatever has previously ailed us.

This account is what should happen when the new coronavirus enters the body, based on general knowledge about the immune system and how it reacts to other respiratory viruses. But what actually happens? Well … sigh … the thing is, the immune system is very complicated.

In general, the immune system’s reaction to SARS-CoV-2 is “what I would expect if you told me there was a new respiratory infection,” says Shane Crotty from the La Jolla Institute of Immunology. The innate immune system switches on first, and the adaptive immune system follows suit. In several studies, most people who are infected develop reasonable levels of coronavirus-specific T-cells and antibodies. “The bottom line is that there are no big surprises,” says Sarah Cobey, an epidemiologist from the University of Chicago.

Still, “any virus that can make people sick has to have at least one good trick for evading the immune system,” Crotty says. The new coronavirus seems to rely on early stealth, somehow delaying the launch of the innate immune system, and inhibiting the production of interferons—those molecules that initially block viral replication. “I believe this [delay] is really the key in determining good versus bad outcomes,” says Akiko Iwasaki, an immunologist at Yale. It creates a brief time window in which the virus can replicate unnoticed before the alarm bells start sounding. Those delays cascade: If the innate branch is slow to mobilize, the adaptive branch will also lag.

Many infected people still clear the virus after a few weeks of nasty symptoms. But others don’t. Maybe they initially inhaled a large dose of virus. Maybe their innate immune systems were already weakened through old age or chronic disease. In some cases, the adaptive immune system also underperforms: T-cells mobilize, but their levels recede before the virus is vanquished, “almost causing an immunosuppressed state,” Iwasaki says. This dual failure might allow the virus to migrate deeper into the body, toward the vulnerable cells of the lungs, and to other organs including the kidneys, blood vessels, and the gastrointestinal and nervous systems. The immune system can’t constrain it, but doesn’t stop trying. And that’s also a problem.

Immune responses are inherently violent. Cells are destroyed. Harmful chemicals are unleashed. Ideally, that violence is targeted and restrained as Metcalf puts it, “Half of the immune system is designed to turn the other half off.” But if an infection is allowed to run amok, the immune system might do the same, causing a lot of collateral damage in its prolonged and flailing attempts to control the virus.

This is apparently what happens in severe cases of COVID-19. “If you can’t clear the virus quickly enough, you’re susceptible to damage from the virus and the immune system,” says Donna Farber, a microbiologist at Columbia. Many people in intensive-care units seem to succumb to the ravages of their own immune cells, even if they eventually beat the virus. Others suffer from lasting lung and heart problems, long after they are discharged. Such immune overreactions also happen in extreme cases of influenza, but they wreak greater damage in COVID-19.

There’s a further twist. Normally, the immune system mobilizes different groups of cells and molecules when fighting three broad groups of pathogens: viruses and microbes that invade cells, bacteria and fungi that stay outside cells, and parasitic worms. Only the first of these programs should activate during a viral infection. But Iwasaki’s team recently showed that all three activate in severe COVID-19 cases. “It seems completely random,” she says. In the worst cases, “the immune system almost seems confused as to what it’s supposed to be making.”

No one yet knows why this happens, and only in some people. Eight months into the pandemic, the variety of COVID-19 experiences remains a vexing mystery. It’s still unclear, for example, why so many “long-haulers” have endured months of debilitating symptoms. Many of them have never been hospitalized, and so aren’t represented in existing studies that have measured antibody and T-cell responses. David Putrino of Mount Sinai tells me that he surveyed 700 long-haulers and a third had tested negative for antibodies, despite having symptoms consistent with COVID-19. It’s unclear if their immune systems are doing anything differently when confronted with the coronavirus.

We should expect such mysteries to build. The immune system’s reaction to the virus is a matter of biology, but the range of reactions we actually see is also influenced by politics. Bad decisions mean more cases, which means a wider variety of possible immune responses, which means a higher prevalence of rare events. In other words, the worse the pandemic gets, the weirder it will get.

A few patterns offer easier possible explanations. “Kids have very trigger-happy innate immune systems,” says Florian Krammer of Mount Sinai’s Icahn School of Medicine, which might explain why they rarely suffer severe infections. Elderly people are less fortunate. They also have smaller standing pools of T-cells to draw from, as if the mercenary-filled bar from the earlier metaphor is only sparsely packed. “It takes longer for the adaptive response to mobilize,” Farber says.

There are also preliminary hints that some people might have a degree of preexisting immunity against the new coronavirus. Four independent groups of scientists—based in the U.S., Germany, the Netherlands, and Singapore—have now found that 20 to 50 percent of people who were never exposed to SARS-CoV-2 nonetheless have significant numbers of T-cells that can recognize it. These “cross-reactive” cells likely emerged when their owners were infected by other, related coronaviruses, including the four mild ones that cause a third of common colds, and the many that infect other animals.

But Farber cautions that having these cross-reactive T-cells “tells you absolutely nothing about protection.” It’s intuitive to think they would be protective, but immunology is where intuition goes to die. The T-cells might do nothing. There’s an outside chance that they could predispose people to more severe disease. We can’t know for sure without recruiting lots of volunteers, checking their T-cell levels, and following them over a long period of time to see who gets infected—and how badly.

Even if the cross-reactive cells are beneficial, remember that T-cells act by blowing up infected cells. As such, they’re unlikely to stop people from getting infected in the first place, but might reduce the severity of those infections. Could this help to explain why, politics aside, some countries had an easier time with COVID-19 than others? Could it explain why some people incur only mild symptoms? “You can go pretty crazy pretty quickly with the speculations,” says Crotty, who co-led one of the studies that identified these cross-reactive cells. “A lot of people have latched onto this and said it could explain everything. Yes, it could! Or it could explain nothing. It’s a really frustrating situation to be in.”

“I wish it wasn’t,” he adds, “but the immune system is really complicated.”

One of the most pressing mysteries is what happens after you’re infected—and whether you could be again. Crucially, researchers still don’t know how much protection the leftover antibodies, T-cells, and memory cells might offer against COVID-19, or even how to measure that.

In July, a team of British researchers released a study showing that many COVID-19 patients lose substantial levels of their coronavirus-neutralizing antibodies after a few months. An earlier Chinese study, published in June, found similar results. Both prompted cascades of alarming headlines, which raised concerns that people could be infected repeatedly, or even that a vaccine—many of which work by readying neutralizing antibodies—won’t provide long-term protection. But many of the immunologists I spoke with weren’t too concerned, because—and reassuringly this time—the immune system is really complicated.

First, declines are expected. During an infection, antibodies are produced by two different groups of B-cells. The first group is fast and short-lived, and quickly unleashes a huge antibody tsunami before dying off. The second group is slower but long-lasting, and produces gentler antibody swells that continuously wash over the body. The transition from the first group to the second means that antibody levels usually decline over the course of an infection. “There’s nothing scary about it,” Krammer says.

Taia Wang of Stanford is a little less sanguine. She tells me several studies, including upcoming ones, consistently show that many people seem to lose their neutralizing antibodies after a couple of months. “If you asked me to guess six months ago, I would have thought that they would last longer,” she says. “The durability is not what we’d like.”

But “the fact that you don’t have measurable antibodies doesn’t mean that you aren’t immune,” Iwasaki says. T-cells could continue to provide adaptive immunity even if the antibodies tap out. Memory B-cells, if they persist, could quickly replenish antibody levels even if the current stocks are low. And, crucially, we still don’t know how many neutralizing antibodies you need to be protected against COVID-19.

Wang agrees: “There’s a common notion that antibody quantity is all that matters, but it’s more complicated than that,” she says. “The quality of the antibody is as important.” Quality might be defined by which part of the virus the antibodies stick to, or how well they stick. Indeed, many people who recover from COVID-19 have low levels of neutralizing antibodies overall, but some of them neutralize very well. “Quantity is easier to measure,” Wang adds. “There are more ways to characterize quality and we don’t know which ones are relevant.” (This problem is even worse for T-cells, which are much harder than antibodies to isolate and analyze.)

These uncertainties strengthen the need for large, careful vaccine trials: Right now it’s hard to know whether the promising signs in early trials will actually lead to substantial protection in practice. (Developing and deploying vaccines is a subject for another piece, which my colleague Sarah Zhang has written.) Scientists are trying to work out how to measure COVID-19 immunity by studying large groups of people who have either been infected naturally or taken part in a vaccine trial. Researchers will repeatedly measure and analyze the volunteers’ antibodies and T-cells over time, noting if any of them become infected again. Krammer expects that results will take a few months, or possibly until the end of the year. “There’s no way to speed that up,” he says. Because … well, you know.

In the meantime, anecdotal reports have described alleged reinfections—people who apparently catch COVID-19 a second time, and who test positive for the coronavirus again after months of better health. Such cases are concerning, but hard to interpret. Viral RNA—the genetic material that diagnostic tests detect—can stick around for a long time, and people can test positive for months after they’ve cleared the actual virus. If someone like that caught the flu and went to their doctor, they might get tested for coronavirus again, get a positive result, and be mistakenly treated as a case of reinfection. “It’s really hard to prove reinfection unless you sequence the genes of the virus” both times, Iwasaki says. “No one has that data, and it’s unreasonable to expect.”

Immunity lasts a lifetime for some diseases—chickenpox, measles—but eventually wears off for many others. As the pandemic drags on, we should expect at least a few instances in which people who’ve beaten COVID-19 must beat it again. So far, the fact that reinfections are still the subject of smattered anecdotes suggests that “it’s happening at a very low rate, if at all,” Cobey says. But remember: A bigger pandemic is a weirder pandemic. When there are almost 5 million confirmed cases, something that occurs just 0.1 percent of the time will still affect 5,000 people.

If people endure a second bout with COVID-19, the outcome is again hard to call. For some diseases, like dengue, an antibody response to one infection can counterintuitively make the next infection more severe. So far, there’s no evidence this happens with SARS-CoV-2, says Krammer, who expects that any reinfections would be milder than the first ones. That’s because the coronavirus has a longer incubation time—a wider window between infection and symptoms—than, say, the flu. That could conceivably provide more time for memory cells to mobilize a new force of antibodies and T-cells. “Even if there’s some immunity loss in the future, it’s not that we’d have to go through this pandemic again,” Cobey says.

What will determine our future with the virus is how long protective immunity lasts. For severe coronaviruses like MERS and the original SARS, it persists for at least a couple of years. For the milder coronaviruses that cause common colds, it disappears within a year. It’s reasonable to guess that the duration of immunity against SARS-CoV-2 lies within those extremes, and that it would vary a lot, much like everything else about this virus. “Everyone wants to know,” says Nina Le Bert from the Duke-NUS in Singapore. “We don’t have the answer.”

Most people still haven’t been infected a first time, let alone a second. The immediate uncertainty around our pandemic future “doesn’t stem from the immune response,” Cobey says, but from “policies that are enacted, and whether people will distance or wear masks.” But for next year and beyond, modeling studies have shown that the precise details of the immune system’s reactions to the virus, and to a future vaccine, will radically affect our lives. The virus could cause annual outbreaks. It might sweep the world until enough people are vaccinated or infected, and then disappear. It could lie low for years and then suddenly bounce back. All of these scenarios are possible, but the range of possibilities will narrow the more we learn about the immune system.

That system may be vexingly complex, but it is also both efficient and resilient in a way that our society could take lessons from. It prepares in advance, and learns from its past. It has many redundancies in case any one defense fails. It acts fast, but has checks and balances to prevent overreactions. And, in the main, it just works. Despite the multitude of infectious threats that constantly surround us, most people spend most of the time not being sick.

Cytokine storm and lung damage

The cytokine release syndrome (CRS) seems to affect patients with severe conditions. Since lymphocytopenia is often seen in severe COVID-19 patients, the CRS caused by SARS-CoV-2 virus has to be mediated by leukocytes other than T cells, as in patients receiving CAR-T therapy a high WBC-count is common, suggesting it, in association with lymphocytopenia, as a differential diagnostic criterion for COVID-19. In any case, blocking IL-6 may be effective. Blocking IL-1 and TNF may also benefit patients. Although various clinical sites in China have announced the use of mesenchymal stromal/stem cells (MSCs) in severe cases with COVID-19 infection, solid results have yet to be seen. One caveat is that MSCs need to be activated by IFNγ to exert their anti-inflammatory effects, which may be absent in severely affected patients as T cells are not well activated by SARS-CoV-2 infection. To enhance effectiveness, one could consider employing the “licensing-approach”: pretreat MSCs with IFNγ with/without TNF or IL-1 [5]. Such cytokine-licensed MSCs could be more effective in the suppression of hyperactive immune response and promotion of tissue repair, as licensed-MSCs are effective in LPS-induced acute lung damage [6].

Lung damage is a major hurdle to recovery in those severe patients. Through producing various growth factors, MSCs may help repair of the damaged lung tissue. It is important to mention that various studies have shown that in animal models with bleomycin-induced lung injury, vitamin B3 (niacin or nicotinamide) is highly effective in preventing lung tissue damage [7]. It might be a wise approach to supply this food supplement to the COVID-19 patients.

A memorable infection

When a pathogen breaches the body’s barriers, the immune system will churn out a variety of immune molecules to fight it off. One subset of these molecules, called antibodies, recognizes specific features of the bug in question and mounts repeated attacks until the invader is purged from the body. (Antibodies can also be a way for clinicians to tell if a patient has been recently infected with a given pathogen, even when the microbe itself can no longer be detected.)

Though the army of antibodies dwindles after a disease has resolved, the immune system can whip up a new batch if it sees the same pathogen again, often quashing the new infection before it has the opportunity to cause severe symptoms. Vaccines safely simulate this process by exposing the body to a harmless version or piece of a germ, teaching the immune system to identify the invader without the need to endure a potentially grueling disease.

From the immune system’s perspective, some pathogens are unforgettable. One brush with the viruses that cause chickenpox or polio, for instance, is usually enough to protect a person for life. Other microbes, however, leave less of an impression, and researchers still aren’t entirely sure why. This applies to the four coronaviruses known to cause a subset of common cold cases, says Rachel Graham, an epidemiologist and coronavirus expert at the University of North Carolina at Chapel Hill. Immunity against these viruses seems to wane in a matter of months or a couple of years, which is why people get colds so frequently.

Because SARS-CoV-2 was only discovered recently, scientists don’t yet know how the human immune system will treat this new virus. Reports have surfaced in recent weeks of people who have tested positive for the virus after apparently recovering from COVID-19, fueling some suspicion that their first exposure wasn’t enough to protect them from a second bout of disease. Most experts don’t think these test results represent reinfections. Rather, the virus may have never left the patients’ bodies, temporarily dipping below detectable levels and allowing symptoms to abate before surging upward again. Tests are also imperfect, and can incorrectly indicate the virus’ presence or absence at different points.

Because the COVID-19 outbreak is still underway, “if you’ve already had this strain and you’re re-exposed, you would likely be protected,” says Taia Wang, an immunologist and virologist at Stanford University and the Chan Zuckerberg Biohub. Even antibodies against the most forgettable coronaviruses tend to stick around for at least that long.

COVID-19 packs a stronger punch than the common cold, so antibodies capable of fending off this new coronavirus may have a shot at lingering longer. Broadly speaking, the more severe the disease, the more resources the body will dedicate to memorizing that pathogen’s features, and the stronger and longer lasting the immune response will be, says Allison Roder, a virologist at New York University. Previous studies have shown that people who survived SARS, another coronavirus disease that resulted in a 2003 epidemic, still have antibodies against the pathogen in their blood years after recovery. But this trend is not a sure thing, and scientists don’t know yet whether SARS-CoV-2 will fall in line.

Earlier this month, a team of researchers posted a study (which has yet to be published in a peer-reviewed journal) describing two rhesus macaques that could not be reinfected with SARS-CoV-2 several weeks after recovering from mild bouts of COVID-19. The authors chalked the protection up to the antibodies they found in the monkeys’ bodies, apparently produced in response to the virus—a result that appears to echo the detection of comparable molecules in human COVID-19 patients.

But the mere presence of antibodies doesn’t guarantee protection, Wang says. Reinfections with common cold coronaviruses can still happen in patients who carry antibodies against them. And a bevy of other factors, including a person’s age and genetics, can drastically alter the course of an immune response.

An evolving virus?

Complicating matters further is the biology of SARS-CoV-2 itself. Viruses aren’t technically alive: While they contain genetic instructions to make more of themselves, they lack the molecular tools to execute the steps, and must hijack living cells to complete the replication process for them.

After these pathogens infect cells, their genomes often duplicate sloppily, leading to frequent mutations that persist in the new copies. Most of these changes are inconsequential, or evolutionary dead ends. Occasionally, however, mutations will alter a viral strain so substantially that the immune system can no longer recognize it, sparking an outbreak—even in populations that have seen a previous version of the virus before. Viruses in the influenza family are the poster children for these drastic transformations, which is part of why scientists create a new flu vaccine every year.

When flu viruses copy their genomes, they often make mistakes. These errors can change the way their proteins look to the immune system, helping the viruses evade detection. (Rebecca Senft, Science in the News)

Some viruses have another immunity-thwarting trick as well: If a person is infected with two different strains of the flu at the same time, those viruses can swap genetic material with each other, generating a new hybrid strain that doesn’t look like either of its precursors, allowing it to skirt the body’s defenses.

Researchers don’t yet know how quickly similar changes could occur in SARS-CoV-2. Unlike flu viruses, coronaviruses can proofread their genomes as they copy them, correcting mistakes along the way. That feature reduces their mutation rate, and might make them “less of a moving target” for the immune system, says Scott Kenney, an animal coronavirus expert at Ohio State University. But coronaviruses still frequently trade segments of their genetic code with each other, leaving the potential for immune evasion wide open.

So far, SARS-CoV-2 also doesn’t appear to be undergoing any extreme mutations as it sweeps across the globe. That may be because it’s already hit on such a successful strategy, and doesn’t yet need to change its tactic. “Right now, it’s seeing a completely naive population” that’s never been exposed to the virus before, Graham says. The virus “doesn’t seem to be responding to any kind of pressure,” she adds.

Should SARS-CoV-2 get a second infectious wind, it may not come for some time. Even fast-mutating influenza strains can take years to reenter populations. And if or when that day comes, future COVID-19 outbreaks could be milder. Sometimes viral success means treading gently with the host, says Catherine Freije, a virologist at Harvard University.

“Viruses that causes severe disease actually tend to die out faster because a host that’s feeling ill can’t spread it as well.” In those cases, she says, sometimes, “the outbreak just sort of fizzles out.”

But we can’t rule out the possibility that SARS-CoV-2 could change in a way that bumps up its virulence instead, Kenney says. To steel the population for what’s ahead, sometimes, he adds, “We just have to be the ultimate pessimist when it comes to this type of outbreak.”

Final conclusions and future steps to be taken

Based on the previous discussion points, it is shown that a vaccine stays as the most viable strategy to offer herd immunity for all healthy adults, adolescents, and children that is safe and necessary in order to protect those who could not access the vaccine or are too ill to build up natural immunity. Still, the generation of an appropriate vaccine is presumed to be a minimum of one year away prior to finally reaching the mass distribution process.

Therefore, extended efforts will be required to stop any further catastrophes caused by the COVID-19 pandemic until a scientific discovery occurs. The top arrangements that all governments could consider would be to make sure that the general public stays up-to-date with the important news, have suitable access to the diagnostic tools whenever needed, and to continually promote social distancing in order to curb the transmission of the contagious SARS-CoV-2.

5. Probiotics in the Management of Various Pathologies: Perspectives in COVID-19

5.1. Probiotics in Digestive Tract Pathology

Diarrhea secondary to prolonged administration of antibiotics is a common side effect caused by an imbalance of the intestinal microbiota. The most common pathogen is Clostridioides difficile, which through resistance to antibiotics causes infection of the large intestine [204].

Vanderhoof et al. studied the efficacy of Lactobacillus casei subsp. rhamnosus (Lactobacillus GG) (LGG) in reducing the incidence of antibiotic-associated diarrhea when co-administered with an oral antibiotic in children with acute infectious disorders. The study was done randomized double-blindly on 25 children with diarrheal disease in the end, LGG reduced the incidence of antibiotic-associated diarrhea in children treated with oral antibiotics for common childhood infections [205].

Antibiotics can cause a microbial imbalance in the gut resulting in antibiotic-associated diarrhea (AAD). Probiotics can prevent AAD by rebalancing the intestinal microflora, repairing the intestinal barrier, etc.

Probiotics are increasingly used to prevent and treat diarrheal disease more in children than in adults.

Guarino et al. undertook research on randomized controlled trials of digestive pathology that included: acute gastroenteritis, antibiotic-associated diarrhea (AAD), and necrotic enterocolitis (NE) [206]. In acute gastroenteritis he found 12 studies: 5 with recommended probiotics and 7 not. LGG and Saccharomyces boulardii had the most convincing evidence of efficacy, as they reduced the duration of the disease by one day. For AAD, 4 meta-analyzes were found, which show the variable efficacy of probiotics in preventing diarrhea, depending on the patient’s age and the antibiotic used. The most effective strains were LGG and S. boulardii. In the case of NE, 12 studies were analyzed (of which 3 were randomized controlled trials) and it was found that probiotics reduced the risk of NE and mortality in premature infants. The guidelines did not support routine use of probiotics and requested additional data for such sensitive implications. Research proved there is strong and solid evidence of the effectiveness of probiotics as an active treatment of gastroenteritis in addition to rehydration. There is strong evidence that probiotics have some effectiveness in preventing AAD, but the exact dose needed for treatment is a problem. For both etiologies LGG and S. boulardii have the strongest evidence. In the NE, indications are more debated, but based on available data and their implications, probiotics should be considered carefully. One of the most common side effects during antibiotics is diarrhea. Probiotics are living micro-organisms that, after oral ingestion, can prevent antibiotic-associated diarrhea by normalizing the unbalanced gastrointestinal flora [206].

A meta-analysis was performed by Blaabjerg et al. [204] on the benefits and side effects of probiotics used to prevent AAD in an outpatient setting. A search of the PubMed database was performed and a total of 3631 subjects were included in the analysis. The cumulative results found that 8.0% of the probiotic group with LGG and S. boulardii strains had AAD, compared to 17.7% in the control group. No statistically significant differences were demonstrated in terms of the incidence of side events. The results suggest that the use of probiotics may be good and safe in preventing AAD.

Guo et al. evaluated the efficacy and safety of probiotics used to prevent AAD in children. Thirty-three studies were included (6352 participants) by search: MEDLINE, Embase, CENTRAL, CINAHL, and Web of Science (as of 28 May 2018), including ISRCTN and The probiotics evaluated included Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp. Leuconostoc cremoris, Saccharomyces spp. or Treptococcus spp., alone or in combination. The results suggest a moderate protective effect of probiotics for the prevention of AAD. Using five criteria to assess the credibility of the probiotic dose subgroup analysis, the results indicated that the effect of the high-dose probiotic subgroup of over 5 billion colony-forming units (CFUs) per day was credible. Evidence also suggests that probiotics may moderately reduce the duration of diarrhea, a reduction of almost a day. The benefit of high-dose probiotics (e.g., LGG or Saccharomyces boulardii) should be confirmed by a well-designed randomized multicenter study. Adverse event rates were low, and no serious side effects were attributed to probiotics [207].

Analyzing the effect of AAD probiotics concomitantly with the use of antibiotics, Yan et al. showed that two probiotics (LGG and S. boulardii) are effective in preventing pediatric AAD when administered concomitantly with antibiotics. The optimal dose remains unknown, but 5 to 40 billion CFUs per day seems to be the most effective. These appear to be safe in children, with minimal side effects however, serious adverse events have been documented if the children were severely debilitated or immunocompromised [208].

5.2. Probiotics in Pulmonary Viral Infections

Discovery of the human genome and recent innovative high-speed and low-cost sequencing technologies of genes, especially the 16S rRNA gene [209] disturbed the conservative idea that the lung would be sterile.

The concept of lung sterility [210] was supported by laboratory data limited by traditional study techniques by aspiration of secretions and then their culture, which detected a percentage of only 1% of bacteria present in healthy airway samples [209].

Progressive-minded ideas and the accumulation of a huge number of studies on the microbiota in the last decade have reformed our understanding of the existence of the lung microbiota and the lung–microbiota axis (relationship) [211].

More and more studies provide evidence of the strong relationship between the intestinal microbiota and many human diseases [6], and the recognition in depth of the dual host-microbe interaction mechanisms in the intestine and lung is a necessity, to be able to prevent, detect and apply in diseases therapy [212].

The pulmonary microbiota plays a particularly important role in preserving the homeostasis of the respiratory system, to promote and preserve a state of immune tolerance, to prevent an unwanted inflammatory reaction after inhalation of harmless environmental agents. This activity is supported by an indestructible and permanent link between the microbiota and the immune cells in the lungs, which through specialized sensors detect invasive micro-organisms [213].

The oropharynx and the upper respiratory tract are permanently invaded by microbes that through direct communication and subclinical aspiration of the oropharyngeal content, enter the lungs and form the bacterial microbiome in various anatomical sites.

Changes in the lung microbiome through which dysbiosis can occur, will influence the host’s immunity and defense understanding these complex interactions between the host and the pathogen elucidates the pathogenesis of chronic lung disease [214].

Once the respiratory tract infection has occurred, the commensal microbial flora acts locally on the lungs and on the intestine-lung axis and an adjacent immune response occurs [212].

Laboratory research on murine has shown that the bacterial flora in the lungs grows immediately after birth, so at 15 days we find fewer strands of Gammaproteobacteria and Firmicutes, and many more Bacteroidetes [215].

During the development and growth of the infant and later the child, the lung is increasingly populated with various bacteria, up to the mature microbiota.

Experimental studies have shown that between the intestinal microbiota and the segments of the respiratory system there is an interconnected relationship, for example: disruption of the intestinal microbiota in mice by antibiotics led to increases in fungal colonies, which exaggerated the immune response (increased eosinophils, mast cells, serum levels of IL-5, IL-13, IFN-γ, IgE) allergic to intranasal provocation with Aspergillus fumigatus [216].

Administration of probiotics for the modulation of the intestinal microbiota in Macaque monkeys led to an increase in the number of B lymphocytes expressing IgAs in the colon and in the lymph nodes, probably as a response to the growth of T-helper follicular cells (Tfh) and IL-23 expression in dendritic cells [217].

Acute infections of the upper respiratory tract and lung of viral etiology (adenovirus, rhinovirus, influenza, enterovirus, coronavirus) then complicated bacterially, is a major public health problem worldwide, a major cause of debility, chronicity and death in children and adults [218].

RNA viral agents are known to be extremely contagious and can cause respiratory infections such as Severe Acute Respiratory Syndrome (SARS) and even a pandemic, such as the current 𠇌oronavirus disease 2019” (COVID-19), a contagious infection produced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [219].

In this pathology, the best attitude is to prevent viral infections knowing that antiviral drugs are few, and vaccines are limited.

Probiotics can be a valuable alternative for preventing and ameliorating respiratory tract infections with viral agents, which cause so many diseases in children and adults.

Maeda et al. studied the effect of the oral Lactobacillus plantarum L-137 (HK-LP) probiotic in mice infected with intranasal administration of influenza A/FM/1/47 virus (H1N1, a mouse-adapted strain). They found that clinically, survival time was prolonged in the probiotic group and that viral titers were significantly lower than in the control group. Biologically, an elevated level of interferon beta (IFN-β) was demonstrated in HK-LP-treated mice, while in the control group it was undetectable. The authors concluded that the probiotic HK-LP was beneficial in preventing the spread of influenza infection by inducing IFN-β synthesis [220].

Several in vitro and in vivo studies in mice have shown that HK-LP, an isolated strain of fermented food, was a potent stimulant for the synthesis of cytokines IL-12 and tumor necrosis factor alpha (TNF) -α) [102,221,222,223].

Hori et al. [224] demonstrated that intranasal administration of Lactobacillus casei strain Shirota (LcS), produces a strong release of IL-12, interferon-gamma (IFN-γ) and TNF-α, which have an important effect in eliminating influenza virus from mediastinal ganglion cells. Reducing the virus titer in the upper respiratory tract to 1/10 compared to the control group was valuable in preventing the death of the studied mice. This study suggests that intranasal administration of LcS improves the level of cellular immunity in the respiratory tract and prevents infection with influenza virus.

Lehtoranta et al. [225] conducted a review of the effects of probiotics administration (Lactobacillus, Bifidobacterium, Lactococcus) on viral respiratory tract infections in animal models and clinical trials, and found promising data demonstrating that specific probiotics can shorten the duration or reduce the risk of respiratory infections.

Arshad et al. [226] in a recently published mini review, show that the use of plant-based foods in the daily diet with high levels of minerals such as magnesium, zinc, micronutrients, vitamins C, D, and E, along with a good lifestyle, increase the number of good intestinal bacteria that boost the immune system and can control the onset of respiratory viral infections, including COVID-19.

Pulmonary microbiota, characterized for several years as a much smaller biomass than the intestinal one, is constantly changing in the situation of respiratory disorders and is immunomodulated by the intestinal one, on the gut–lung axis.

A material reviewed by Dumas et al. [227] highlights the beneficial role of commensal bacteria in the body in acute viral diseases of the respiratory tract and presents evidence of the contribution of bacteria to local immunity of the lungs or gut.

5.3. Probiotics and COVID-19

Recent studies show that although SARS-CoV-2 infection is a disease with initial respiratory manifestations, there are data that revealed the close relationship between the intestinal microbiome and the severity of clinical manifestations in patients with COVID-19.

In a cohort study in two hospitals, per 100 patients with laboratory-confirmed SARS-CoV-2 infection, conducted by Yeoh et al., the compositions of the intestinal microbiome were evaluated by shotgun-sequencing total DNA extracted from stools, as well as the levels of inflammatory cytokines and biological markers. Commensal bacteria with immunomodulatory potential (Faecalibacterium prausnitzii, Eubacterium rectale, Bifidobacterium), were underrepresented and correlated with the severity of the infection, elevated levels of cytokines and inflammatory blood markers (CRP, LDH, aspartate aminotransferase, and gamma-glutamyl transferase). Maintaining the imbalance of the intestinal microbiota (dysbiosis) after the cure of the acute viral infection could be the cause of persistent and long-lasting COVID symptoms [228].

Balancing the intestinal microbiota during and after viral infections can be achieved with the help of probiotics that adhere and line the intestinal mucosa, constituting a strong barrier against pathogens and at the same time, activate the immune system.

It is known that the intestinal microbiota acts on alveolar macrophages and on the intestine-lung axis and develops a defense system against bacterial and viral infections [229].

When an infection occurs in the lungs, the alarm signals are transmitted from the lung to the intestine on the lung-gut axis and from there, the information is transmitted further to the central nervous system (brain) on the gut𠄻rain axis, to stop the inflammatory processes. These data are processed in the cerebral cortex and sent back on the brain–lung–intestine axis, so that the defense processes are implemented in this way, the microbiota, through its bacterial complexity, mobilizes itself to defend the lung.

Medical research highlights the existence of complex functional connections between lungs and brain, specialized cells transmitting nerve impulses-mediated communication, as an entity made up of related parts via neuroendocrine, immune, and inflammatory networks, the gut𠄻rain–lung axis [230].

Pathophysiology of lungs and intestines is intricately linked, so that an abnormal function in any of them will cause the installation of the disease in the other. The bidirectionality on the lung–intestine axis is accomplished through the products of the microbial metabolism and endotoxins from the gut that reach via bloodstream the lungs, and vice versa, the products of the inflammatory processes in the lungs, will act on the intestinal microbiota [231].

Probiotics act as immunomodulators, stimulate the protection of the host, and can affect the occurrence and severity of disorders at a distance from the intestine.

Oral probiotics have been shown to control respiratory immune reactions.

Probiotics and their mechanisms of action in the prevention and treatment of respiratory diseases, could bring great benefits in the COVID-19 pandemic.

In an experiment conducted by Harata et al. on BALB/c mice infected with influenza virus IFV A/PR/8/34 (H1N1), who were administered intranasally the probiotic LGG, it was found that LGG reduced the respiratory symptoms, increased survival rate compared to the control group and improved the immune responses by increasing the activation of natural killer (NK) lung cells [232].

Severe lung infection with SARS-Cov-2 that binds to ACE2 receptors in lung epithelial cells, has effects also on the intestinal microbiota, by binding of the virus to ACE2 receptors on the enterocytes of the small intestine, so that the SARS-CoV-2 RNA was found in the stool of the infected patients.

Given the bidirectional transmission of information on the gut–lung axis, complex interventions through prebiotics, probiotics, postbiotics, parabiotics, synbiotics, and a personalized diet could modulate the microbiome, improve the immune system activity, and save lives, especially in the elderly and/or debilitated, people with low immunity [231].

De Marcken et al. investigated the activation and response of human blood CD14+ monocytes to single-stranded RNA viruses as being virus-specific and differentially involving the Toll-like receptors (TLRs), TLR7 and TLR8, which triggered different signaling pathways in monocytes, well correlated with the production of cytokines involved in the polarization of CD4+ T-helper cells.

Also, only TLR7 stimulated Ca2+ influx that impede the type-I IFN responses. This study reveals the different signaling pathways activated by TLR7 and TLR8 in human monocytes promoting distinctive T-helper and antiviral replies and specific characteristics during RNA virus infection [233].

After infection with the RNA virus SARS-CoV-2, the body responds through the innate defense system (TLR) that is activated, and through inflammatory pathways, as a defense shield (NLRP3 and NF-㮫). Set in motion TLRs trigger the first-incidence antiviral reactions through MYD88—the canonical adapter for inflammatory signaling pathways downstream of members of the Toll-like receptor, and IRF3/7-connected type-I IFN production. As a response to infection and cellular damage, the inflammasome NLRP3, a particular constituent of the innate immune system, coordinates the activation of caspase-1 and the release of pro-inflammatory cytokines IL-1β/IL-18, and under the action of the latter are activated T-cells and macrophages that will secrete IL-6 and TNFα. The IL1B, IL18, IL-6 and TNFα transform supplementary other naïve T-cells into Th1/CTLs/CD8+ or Th17, which generate pro-inflammatory cytokines IFNγ and IL17 [234].

Native and acquired immune responses against infectious viral agents of the respiratory tract are supervised on the bidirectional gut–lung axis by the intestinal microbiome [235].

NF-㮫, activated by NLRP3 or TLR4 and the stress-induced mitogen-activated protein kinase (MAPK or MAP kinase) signaling pathway, assists the generation of pro-inflammatory cytokines and apoptosis in enterocytes, but also in lung tissues. Elements resulting from the destruction of tissues following the conflict with the pathogen promote the activation of the innate immune system and an uncontrolled and excessive release of pro-inflammatory signaling molecules, the cytokine storm, i.e., the sudden release in large quantities of cytokines, which can cause multisystem organ failure and death [236].

Some probiotics have been shown to balance the activity of the immune system and inhibit the secretion of pro-inflammatory cytokines, with special implications in the management of COVID-19 and the cytokine storm induced by SARS-CoV-2 infection in severe cases [237].

Kwon et. al. investigated the effects of a cocktail of five probiotics, L. acidophilus, L. casei, L. reuteri, B. bifidium and Streptococcus thermophilus that proved to be capable of up-regulating the CD4+ Foxp3+ regulatory T-cells (Tregs), to diminish the degree of responsiveness in T-cells and B-cells, and down-regulated T-helper (Th) 1, Th2, and Th17 cytokines, without provoking apoptosis. The probiotics increased the number of dendritic cells with regulatory properties that expressed high levels of IL-10, TGF-β, COX-2 and promoted the generation of regulatory T-cells, also rising the suppressor activity of naturally occurring CD4 + CD25 + Tregs [238].

Recent literature draws attention to the beneficial effects of oral probiotics in preventing and modulating the severity of clinical manifestations of viral respiratory infections.

In the current stage of the COVID-19 pandemic, when there are still no specific drugs for SARS-CoV-2 infection, it would be especially useful to administer known probiotics with antiviral action proven by randomized and placebo-controlled clinical scientific studies.

Studies are needed on the use of probiotics with the concomitant administration of prebiotic oligosaccharides (e.g., fructans, galactans) with the role of enhancing the probiotic strains and balancing the host microbiota [239].

Coronavirus outbreak raises question: Why are bat viruses so deadly?

It's no coincidence that some of the worst viral disease outbreaks in recent years -- SARS, MERS, Ebola, Marburg and likely the newly arrived 2019-nCoV virus -- originated in bats.

A new University of California, Berkeley, study finds that bats' fierce immune response to viruses could drive viruses to replicate faster, so that when they jump to mammals with average immune systems, such as humans, the viruses wreak deadly havoc.

Some bats -- including those known to be the original source of human infections -- have been shown to host immune systems that are perpetually primed to mount defenses against viruses. Viral infection in these bats leads to a swift response that walls the virus out of cells. While this may protect the bats from getting infected with high viral loads, it encourages these viruses to reproduce more quickly within a host before a defense can be mounted.

This makes bats a unique reservoir of rapidly reproducing and highly transmissible viruses. While the bats can tolerate viruses like these, when these bat viruses then move into animals that lack a fast-response immune system, the viruses quickly overwhelm their new hosts, leading to high fatality rates.

"Some bats are able to mount this robust antiviral response, but also balance it with an anti-inflammation response," said Cara Brook, a postdoctoral Miller Fellow at UC Berkeley and the first author of the study. "Our immune system would generate widespread inflammation if attempting this same antiviral strategy. But bats appear uniquely suited to avoiding the threat of immunopathology."

The researchers note that disrupting bat habitat appears to stress the animals and makes them shed even more virus in their saliva, urine and feces that can infect other animals.

"Heightened environmental threats to bats may add to the threat of zoonosis," said Brook, who works with a bat monitoring program funded by DARPA (the U.S. Defense Advanced Research Projects Agency) that is currently underway in Madagascar, Bangladesh, Ghana and Australia. The project, Bat One Health, explores the link between loss of bat habitat and the spillover of bat viruses into other animals and humans.

"The bottom line is that bats are potentially special when it comes to hosting viruses," said Mike Boots, a disease ecologist and UC Berkeley professor of integrative biology. "It is not random that a lot of these viruses are coming from bats. Bats are not even that closely related to us, so we would not expect them to host many human viruses. But this work demonstrates how bat immune systems could drive the virulence that overcomes this."

The new study by Brook, Boots and their colleagues was published this month in the journal eLife.

Boots and UC Berkeley colleague Wayne Getz are among 23 Chinese and American co-authors of a paper published last week in the journal EcoHealth that argues for better collaboration between U.S. and Chinese scientists who are focused on disease ecology and emerging infections.

Vigorous flight leads to longer lifespan -- and perhaps viral tolerance

As the only flying mammal, bats elevate their metabolic rates in flight to a level that doubles that achieved by similarly sized rodents when running.

Generally, vigorous physical activity and high metabolic rates lead to higher tissue damage due to an accumulation of reactive molecules, primarily free radicals. But to enable flight, bats seem to have developed physiological mechanisms to efficiently mop up these destructive molecules.

This has the side benefit of efficiently mopping up damaging molecules produced by inflammation of any cause, which may explain bats' uniquely long lifespans. Smaller animals with faster heart rates and metabolism typically have shorter lifespans than larger animals with slower heartbeats and slower metabolism, presumably because high metabolism leads to more destructive free radicals. But bats are unique in having far longer lifespans than other mammals of the same size: Some bats can live 40 years, whereas a rodent of the same size may live two years.

This rapid tamping down of inflammation may also have another perk: tamping down inflammation related to antiviral immune response. One key trick of many bats' immune systems is the hair-trigger release of a signaling molecule called interferon-alpha, which tells other cells to "man the battle stations" before a virus invades.

Brook was curious how bats' rapid immune response affects the evolution of the viruses they host, so she conducted experiments on cultured cells from two bats and, as a control, one monkey. One bat, the Egyptian fruit bat (Rousettus aegyptiacus), a natural host of Marburg virus, requires a direct viral attack before transcribing its interferon-alpha gene to flood the body with interferon. This technique is slightly slower than that of the Australian black flying fox (Pteropus alecto), a reservoir of Hendra virus, which is primed to fight virus infections with interferon-alpha RNA that is transcribed and ready to turn into protein. The African green monkey (Vero) cell line does not produce interferon at all.

When challenged by viruses mimicking Ebola and Marburg, the different responses of these cell lines were striking. While the green monkey cell line was rapidly overwhelmed and killed by the viruses, a subset of the rousette bat cells successfully walled themselves off from viral infection, thanks to interferon early warning.

In the Australian black flying fox cells, the immune response was even more successful, with the viral infection slowed substantially over that in the rousette cell line. In addition, these bat interferon responses seemed to allow the infections to last longer.

"Think of viruses on a cell monolayer like a fire burning through a forest. Some of the communities -- cells -- have emergency blankets, and the fire washes through without harming them, but at the end of the day you still have smoldering coals in the system -- there are still some viral cells," Brook said. The surviving communities of cells can reproduce, providing new targets for the the virus and setting up a smoldering infection that persists across the bat's lifespan.

Brook and Boots created a simple model of the bats' immune systems to recreate their experiments in a computer.

"This suggests that having a really robust interferon system would help these viruses persist within the host," Brook said. "When you have a higher immune response, you get these cells that are protected from infection, so the virus can actually ramp up its replication rate without causing damage to its host. But when it spills over into something like a human, we don't have those same sorts of antiviral mechanism, and we could experience a lot of pathology."

The researchers noted that many of the bat viruses jump to humans through an animal intermediary. SARS got to humans through the Asian palm civet MERS via camels Ebola via gorillas and chimpanzees Nipah via pigs Hendra via horses and Marburg through African green monkeys. Nonetheless, these viruses still remain extremely virulent and deadly upon making the final jump into humans.

Brook and Boots are designing a more formal model of disease evolution within bats in order to better understand virus spillover into other animals and humans.

"It is really important to understand the trajectory of an infection in order to be able to predict emergence and spread and transmission," Brook said.

The Coronavirus Patients Betrayed by Their Own Immune Systems

A “cytokine storm” becomes an all-too-frequent phenomenon, particularly among the young. But treatments are being tested.

The 42-year-old man arrived at a hospital in Paris on March 17 with a fever, cough and the “ground glass opacities” in both lungs that are a trademark of infection with the new coronavirus.

Two days later, his condition suddenly worsened and his oxygen levels dropped. His body, doctors suspected, was in the grip of a cytokine storm, a dangerous overreaction of the immune system. The phenomenon has become all too common in the coronavirus pandemic, but it is also pointing to potentially helpful drug treatments.

When the body first encounters a virus or a bacterium, the immune system ramps up and begins to fight the invader. The foot soldiers in this fight are molecules called cytokines that set off a cascade of signals to cells to marshal a response. Usually, the stronger this immune response, the stronger the chance of vanquishing the infection, which is partly why children and younger people are less vulnerable over all to coronavirus. And once the enemy is defeated, the immune system is hard-wired to shut itself off.

“For most people and most infections, that’s what happens,” said Dr. Randy Cron, an expert on cytokine storms at the University of Alabama at Birmingham.

But in some cases — as much as 15 percent of people battling any serious infection, according to Dr. Cron’s team — the immune system keeps raging long after the virus is no longer a threat. It continues to release cytokines that keep the body on an exhausting full alert. In their misguided bid to keep the body safe, these cytokines attack multiple organs including the lungs and liver, and may eventually lead to death.

In these people, it’s their body’s response, rather than the virus, that ultimately causes harm.

Cytokine storms can overtake people of any age, but some scientists believe that they may explain why healthy young people died during the 1918 pandemic and more recently during the SARS, MERS and H1N1 epidemics. They are also a complication of various autoimmune diseases like lupus and Still’s disease, a form of arthritis. And they may offer clues as to why otherwise healthy young people with coronavirus infection are succumbing to acute respiratory distress syndrome, a common consequence of a cytokine storm.

Reports from China and Italy have described young patients with clinical outcomes that seem consistent with this phenomenon. It’s very likely that some of these patients developed a cytokine storm, Dr. Cron said.

In the case of the 42-year-old patient, the suspected cytokine storm led his doctors to eventually try tocilizumab, a drug they have sometimes used to soothe an immune system in distress.

After just two doses of the drug, spaced eight hours apart, the patient’s fever rapidly disappeared, his oxygen levels rose and a chest scan showed his lungs clearing. The case report, described in an upcoming paper in Annals of Oncology, joins dozens of accounts from Italy and China, all indicating that tocilizumab might be an effective antidote to the coronavirus in some people.

On March 5, China approved the drug to treat serious cases of Covid-19, the disease caused by the coronavirus, and authorized clinical trials. On March 23, the U.S. Food and Drug Administration granted approval to the pharmaceutical company Roche to test the drug in hundreds of people with coronavirus infection.

Tocilizumab is approved to quieten the chatter of immune molecules in rheumatoid arthritis and in some types of cancer. It mutes the activity of a specific cytokine called interleukin-6 that is associated with an over-exuberant immune response.

“That’s the rationale for using the drug,” said Dr. Laurence Albiges, who cared for the patient at the Gustave Roussy Cancer Center in Paris.

Even as researchers look for treatments, they are trying to learn more about why some people’s immune systems go into this dangerous overdrive. Genetic factors explain the risk, at least in some kinds of cytokine storms.

There are many variations on the phenomenon, and they go by many names: systemic inflammatory response syndrome, cytokine release syndrome, macrophage activation syndrome, hemophagocytic lymphohistiocytosis.

Broadly speaking, they are all marked by an unbridled surge in immune molecules, and may all result in the fatal shutdown of multiple organs.

But many doctors are unfamiliar with this niche concept or how to treat it, experts said.

“Everyone’s talking about cytokine storm as if it were a well-recognized phenomenon, but you could have asked medics two weeks ago and they wouldn’t have heard of it,” said Dr. Jessica Manson, an immunologist at University College London Hospital.

A patient battling a cytokine storm may have an abnormally fast heart rate, fever and a drop in blood pressure. Apart from a surge in interleukin-6, the body may also show high swirling levels of molecules called interleukin-1, interferon-gamma, C-reactive protein and tumor necrosis factor-alpha.

This storm, if it develops, becomes obvious a few days into the infection. But the sooner doctors catch on to it and treat it, the more likely the patient is to survive. Too late, and the storm may be beyond control, or may already have caused too much damage.

There is a relatively simple, rapid and easily available test that can detect whether a patient’s body has been taken over by a cytokine storm. It looks for high levels of a protein called ferritin.

But if the test does suggest a cytokine storm is underway, what then?

The seemingly obvious solution is to quell the storm, Dr. Cron said: “If it’s the body’s response to the infection that’s killing you, you need to treat that.”

The reality is trickier, especially given the lack of reliable data for Covid-19. But noting that drugs like tocilizumab are taken regularly by people with arthritis, Dr. Cron said the benefit would probably outweigh potential harm if someone is facing death.

“We need evidence-based data, but in a pandemic, where we’re flying by the seat of our pants, we always have to treat the patient in front of us,” he said.

Other drugs might also be useful against cytokine storms. For example, a drug called anakinra mutes interleukin-1, another of the wayward proteins. Clinical trials of anakinra for Covid-19 are also underway. A report published this week suggested that hydroxychloroquine, a much-spotlighted malaria drug that also calms an overactive immune response, might also be effective as a treatment for those who are mildly ill from coronavirus.

Doctors could also turn to corticosteroids, which broadly turn down the entire immune response. That poses its own danger, by exposing the patient to other opportunistic infections, especially in a hospital. “It’s about getting the balance right between suppression of the over-exuberant immune response and still allowing the immune response to fight the virus,” Dr. Manson said.

A group of experts convened two weeks ago to discuss the best ways to collect more data and to treat patients who appear to have cytokine storm. It’s already clear that the complexities of the immune system and the course of coronavirus mean there is no single best treatment.

At the Gustave Roussy Cancer Center, doctors treated another coronavirus patient with tocilizumab. That individual did not show any improvement with the drug.

“The response to the pathogen, the virus, is totally different in different individuals,” said Dr. Fabrice André, an oncologist at the center. “The trials will determine in which patients it works.”

Doctor offers coronavirus protection advice

Dr. Leo Galland says he has useful and practical information for those concerned about the present coronavirus epidemic and also to correct some misinformation that is circulating.

NEW YORK - Internist and author of medical books, Leo Galland M.D., has authored this information on what he recommends at coronavirus protection options.

He says he has written this to supply useful and practical information for those concerned about the present coronavirus epidemic and also to correct some misinformation that is circulating:

I have written this to supply useful and practical information for those concerned about the present corona virus pandemic and also to address some misinformation that has been circulating. I have decided to focus on what is unique about COVID-19, as opposed to general anti-viral measures, because the world has not seen anything like this in a hundred years.


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 labeled COVID-19, which has certain distinctive features: Chinese data indicate that 80% of infected people have minimal symptoms and do not seek medical attention, whereas 15% become moderately to severely ill with cough and shortness of breath and 5% require intensive care. About half the Chinese patients admitted to hospitals did not have a fever and a fifth failed to develop fever despite having pneumonia, so—unlike with influenza—the presence or absence of fever is not a useful diagnostic aid. 

COVID-19 appears to spread readily from person to person, usually as droplets from coughing or sneezing.  A cough or sneeze may send a virus-containing droplet as far as 27 feet, coasting on turbulent airflow. A study from the National Institutes of Health found that droplets containing SARS-CoV-2 may remain airborne for 3-4 hours, but they start losing infectivity rapidly. Within 66 minutes, the droplets have lost half their potency. SARS-CoV-2 is also shed in stool, and for a quarter of the people studied it persisted in stool after respiratory swabs had become negative. Food-borne or water-borne infection is possible but not yet demonstrated. Corona viruses remain viable on surfaces for several days (more about this below), but spread of infection from touching of a contaminated surface has not yet been demonstrated.

The incubation period from exposure to illness is 2 to 14 days, with an average of 5 days. Unlike the flu, COVID-19 appears to start gradually with fatigue, aches and pains and a sore throat or mild dry cough or occasionally a stuffed or runny nose, sometimes nausea and loss of appetite. For some people, the first symptom is abdominal pain without respiratory complaints. Loss of smell and taste occurs frequently. Some people experience diarrhea. The initial respiratory symptoms typically last about 5 days and are followed by recovery. This is Phase One, and for 80% of people it is the only phase. ਏor 20%, however, Phase Two starts after 5 days, with increasing cough and shortness of breath, symptoms of pneumonia. Neurological symptoms like seizures and strikes have been described. Whether sick or well, infected people shed the virus in secretions for several weeks and may still be contagious 8 days after symptoms end.

Because people who are infected but not sick are able to infect others, widespread dissemination has already occurred and will continue. For this reason, locations that implemented widespread testing (as in Germany) or early shelter-in-place orders (California, Washington state) are seeing reduced spread and mortality. Despite misleading early reports, morbidity (the degree of illness) is the same for young adults as for those aged 50-65.

Patients hospitalized with COVID-19 are frequently co-infected with bacteria and with other viruses (over 50% in a Chinese retrospective study), so antibiotics may have a positive impact.  The mortality rate of COVID-19 varies with the population being studied. The clearest data for mortality among ambulatory, well-fed individuals comes from the Diamond Princess cruise ship, because all of the 3500 people on board were tested. So far, 706 have tested positive for the virus and 9 have died, a case fatality rate of 1.4%. This is over 10 times greater than the typical seasonal flu. A re-calculation of the case fatality rate in Wuhan produced a similar figure, 1.38%.  The risk of severe illness is greater in men than in women and increases with advancing age, high blood pressure, diabetes, and heart, lung or kidney disease. Immune suppression by itself does not appear to increase morbidity or mortality. Patients receiving cancer chemotherapy or transplant drugs do not show increased risk or severity of corona virus disease.

It is not presently known whether recovery from infection with COVID-19 produces immunity to the virus. There are reports of apparent re-infection, but they might represent inaccuracies of testing or the flare-up of an infection that had been suppressed and not cured. In China, the rate of false negatives for nasal or oral swabs was 10-30%.  


Avoidance of exposure should be the number one strategy and has received the most attention. Methods of avoidance are described in the section below called Anti-Viral Hygiene. By avoiding infection, you help prevent spread to other people and benefit the entire community. Quarantines will delay the spread of infection and reduce the burden on the health care system, but they are not designed to eradicate the virus. Most people in the U.S. are likely to be exposed to COVID-19 over the next year.

If you are exposed, there are measures you can take, based on the biology of the virus, which may diminish the likelihood of severe illness. These are not treatments for disease they are preventive strategies to help place you among the 80% with mild to minimal illness and they have the greatest chance of succeeding if they are implemented before you are exposed. If it becomes possible to expand the 80% with trivial illness from COVID-19 to 90%, the social benefit will be enormous.


In order to cause disease, any virus must enter a human cell, replicate, and damage the cell, escaping to infect adjacent cells. For COVID-19, there are 3 enzymes that play a critical role in this sequence. They are named ACE-2, Furin and 3-CL protease.

COVID-19 enters human cells by attaching to a protein on the cell surface called ACE-2. The pattern of COVID-19 pneumonia on CT scan matches the distribution of ACE-2 in the lungs. ACE-2 is actually an enzyme with strong beneficial effects in the organs that produce it. When corona virus binds to ACE-2, the protein loses its enzyme activity. In the words of one scientist, COVID-19 produces �-2 exhaustion”.  Some scientists believe that ACE-2 exhaustion is responsible for the severity of pneumonia and for catastrophic effects like heart failure, blood clots and circulatory collapse. I believe that all the clinical manifestations of COVID-19 can be traced to ACE-2 destruction by the virus.

Laboratory studies have shown that restoring ACE-2 dramatically reduces the severity of pneumonia in animals with many types of lung injury, infectious or toxic, including those infected with SARS CoV-1, a close relative of SARS-CoV-2. The resilience of ACE-2 may explain the diversity of responses to corona virus infection. ACE-2 activity is highest in young animals and decreases with age. Conditions associated with death from COVID-19 infection (advanced age, diabetes, high blood pressure, heart disease, kidney disease) are all associated with diminished baseline ACE-2 activity. Because the gene for ACE-2 is located on the X-chromosome, women may have more ACE-2 than men. The second phase of COVID-19, the progression from a minor viral illness to severe pneumonia, may reflect ACE-2 exhaustion, occurring several days after the initial symptoms. This protocol for protection will present aids to enhancing ACE-2 resilience.

In order for the COVID-19 virus to lock on ACE-2, the surface of the virus (the viral spike proteins) must first be altered by an enzyme called Furin. Furin is present in all human cells unlike ACE-2, it is not indispensible. Furin plays a role in the spread of cancer and various infections and there are drugs designed to block Furin. Some dietary components and herbal compounds have been shown to inhibit Furin activity. 

A recent detailed analysis of the evolution of this virus through genetic analysis suggests the following conclusion: COVID-19 has been around for a long time as a source of occasional illness in humans. A series of mutations increased its sensitivity to Furin, allowing the virus to bind much more tightly with ACE-2, making it far more contagious and virulent, and creating the present pandemic. This research makes Furin an attractive target for slowing the spread of infection.

Once they have entered human cells, corona viruses produce damage and spread to other cells by creating an enzyme called 3CL protease. Although several enzymes may be involved in viral replication and spread, 3CL protease is the most important for the corona virus family. It has been called “the Achilles heel” of corona virus and is the subject of new anti-viral drug development. Some dietary flavonoids inhibit 3CL protease in laboratory studies and for that reason may limit severity of infection.

In order to accomplish the steps just described, viruses need to avoid the natural, intrinsic protection provided by the human innate immune system, a series of cells and proteins that kill viruses on contact. Corona viruses have many mechanisms for evading the innate immune system, so it isn’t clear that stimulating innate immunity will offer much protection. Weakened innate immunity may increase susceptibility to illness, so measures to optimize innate immunity are warranted. Once pneumonia develops and disease severity increases, the role of the immune system changes. Much of the damage is due to over activity of immune responses, which is termed a “cytokine storm.” Immune modulating therapies need careful handling during Phase Two of COVID-19 infection.


A few dietary components have shown anti-corona virus effects in laboratory studies, including results in animals. Some of these have a long history of human use for treating infections.

Regular aerobic exercise and a plant-based whole foods diet are associated with improved ACE-2 function. Natural substances shown to enhance ACE-2 function include curcumin (a set of flavonoids found in the spice turmeric), resveratrol (a polyphenol found in red grapes and other foods), rosmarinic acid (a polyphenol found in spices like rosemary and oregano), Panax notoginseng (an herb used in some traditional Chinese medicines—the active Panax fractions for strengthening ACE-2 are called saponins), and alpha-lipoic acid (an anti-oxidant). ACE-2 as an enzyme produces a peptide called Ang 1-7, which is responsible for many of its cellular benefits. Ang 1-7 is made up of 7 amino acids and can be absorbed if taken orally. Availability of Ang 1-7 as a nutraceutical is desirable, but presently elusive.

Resveratrol has a number of beneficial effects on corona virus infection beyond ACE-2 support it inhibits the growth of the deadly MERS corona virus by multiple mechanisms. In addition, resveratrol diminishes the kind of inflammation associated with corona virus infection.

Natural substances that inhibit Furin activity include the herb Andrographis paniculata, a staple of traditional Chinese medicine (the active fractions are called andrographolides), the flavonoid luteolin (found in celery, thyme, green peppers and chamomile tea), and an extract of noni leaf (Morinda citrifolia, the leaf not the fruit). In addition to inhibiting Furin, luteolin was shown to directly block the entry of SARS-Co-V-1 into cells by sticking to the surface spike protein.

Elderberry fruit (Sambucus nigra) and the medicinal herb Houttuynia cordataboth inhibit the viral enzyme 3-CL protease and have been shown to inhibit corona virus activity in cells. Elderberry seems to be most effective if started before infection occurs. It may be contra-indicated in Phase Two of COVID-19, because of its immune boosting effects. Elderberries’ 3CL protease inhibition is related to its content of flavonoids, especially those called anthocyanins, and its immune stimulating activity is related to its complex sugars (polysaccharides). If taking elderberry, make sure its flavonoid or anthocyanin content has been standardized. Elderberry extracts are safer than raw elderberry fruit. The leaves, bark and roots of elderberries contain a toxic substance, which is removed by cooking or extraction. Concerns have been raised about the immune stimulating effects of elderberries. These are addressed in the next section, because they apply to all immune enhancing therapies.

There are several dietary flavonoids that inhibit corona virus 3CL protease. The most studied are luteolin and quercetin, which is found in both elderberry and Houttuynia. Food sources of quercetin include onions, apples and many other fruits. Quercetin is presently being studied in China as a drug treatment for COVID-19, based on research initiated at McGill University. Other flavonoids with potent 3CL protease inhibition in laboratory studies include herbacetin, which is primarily found in ground flax seed (not in flax seed oil but in the husk) and theaflavin gallates, which are abundant in black and puerh tea. Green tea and oolong tea were inactive in this study.  As long as you maintain hydration, black tea with elderberry concentrate may be the beverage of choice. Do not add milk to your tea, as milk interferes with theoflavin absorption.

There is a growing consensus that broad-based attempts to enhance immune function will not help and may hurt people suffering from COVID-19. Immune modulation for COVID-19 should vary with the stage of infection: pre-exposure/asymptomatic, Phase One/Phase Two. Some immune enhancers are sufficiently anti-inflammatory that they have a place in each stage others should only be used for prevention or early asymptomatic infection.

For prevention, enhancement of innate immunity is reasonable, given the proclivity of this virus to sicken people who are older and therefore likely to have sub-optimal innate immune defenses. The innate immune system is present at birth and is ready to attack microbes on contact. Its function is supported by adequate sleep and moderate exercise. The most important dietary component for its maintenance is protein. Protein deficiency impairs innate immunity, but there is no evidence that excess dietary protein improves it beyond the effects of a normal healthy diet. Your protein intake in grams should be about half your lean body weight in pounds.

For symptomatic infection, anti-inflammatory approaches that prevent hyper-reactivity of the innate immune system are warranted.  A key driver of the inflammatory damage in COVID-19 is a protein complex called the NLRP3 inflammasome. Quieting this complex should be a major treatment goal.

Pre-illness enhancement of innate immunity: The safest substances are vitamin D, low dose melatonin, probiotics, prebiotics and mushrooms.

Vitamin D. Almost everyone should supplement with Vitamin D through the winter, but the dose needs to be individualized over a range of 1000 to 5000 IU/day. Vitamin D is best absorbed with a large meal. (A recent review cautioned about a possible pro-inflammatory effect of vitamin D. That report failed to recognize the different forms of vitamin D in the body. The common supplemental form of vitamin D is cholecalciferol, or vitamin D3. In the liver D3 is converted to 25-hydroxyvitamin D3, which is the main circulating form of vitamin D. At sites of inflammation and in the kidneys, 25-hydroxyvitamin D is converted to the most active form, calcitriol. Except in cases of severe deficiency, there is little relationship between vitamin D supplementation and levels of calcitriol. No observation that relates calcitriol level to inflammation has any impact on optimal vitamin D3 supplementation).

Melatonin is a hormone made by the pineal gland at the base of the brain. It supports anti-viral immunity and also helps to control NLRP3. Your body makes melatonin in the dark, mostly between 2-3 AM. Melatonin synthesis decreases with age, which may be one factor contributing to the impact of age on the outcome of COVID-19.  Don’t watch late night television or use a video screen after midnight. Limit artificial lighting at night. Cherry juice contains low levels of melatonin (about 40 micrograms in 8 ounces). Drinking cherry juice (about 16 ounces a day) can significantly increase blood levels of melatonin. You can also take low dose melatonin as a supplement, about one half milligram (0.5 mg) around 10 PM. If you get sick, you may need more. At higher doses, melatonin inhibits the NLRP3 inflammasome. The anti-inflammatory effect of melatonin may be enhanced by high doses of vitamin C.

Medicinal and dietary mushrooms contain polysaccharides that can stimulate innate anti-viral immunity. The best to take in anticipation of SARS-CoV-2 exposure are turkey tail (Coriolus or Trametes versicolor) and reishi (Ganoderma lucidum). In addition to enhancing innate immunity, they can stimulate release of immune balancing, anti-inflammatory cytokines.

Probiotics and prebiotics may impact innate immunity by creating a gut microbiome that stimulates the immune system. Research in this area is in its infancy. Prebiotics with the best evidence for immune stimulation include beta-glucans, arabinogalactans and galacto-oligosaccharides. These are readily available as powders. Probiotics with the best evidence for immune stimulation are Lactobacillus species, especially Lactobacillus plantarum, which is found in sauerkraut and other fermented plant foods, and spore-forming bacteria of the genus Bacillus, which are normally found in soil. Several preparations are commercially available. Because COVID-19 has many mechanisms for evading innate immunity, even when it is strong, immune enhancement by itself is not a promising approach for preventing severe infection.

Elderberry polysaccharides have been shown to enhance innate immunity and prevent viral infections in air travelers. To be rich in polysaccharides, the elderberry extract must be produced by ultra filtration, not by solvent extraction.

Several physicians advise that zinc and vitamin A should be taken to prevent or treat COVID-19. My view is that vitamin A and zinc should only be supplemented if blood levels are low, because of the potential toxicity of high levels of these nutrients. Vitamin A may cause liver toxicity. Zinc is much more complex. Zinc has been advocated at doses of 30 to 75 milligrams per day for its alleged direct anti-vital effects and for its inhibition of certain enzymes involved in viral transport and replication. This advice ignores the physiology of zinc. Levels of zinc in plasma, even when they are low, are about 10 times greater than those needed for inhibition of viral enzymes. The concentration of zinc inside cells is over 200 times higher than needed. Almost all the zinc within cells is bound to proteins, so that the concentration of free zinc is negligible, almost a million times lower than what is needed to inhibit viral-associated enzymes. There is no way that zinc supplementation will impact the level of free intracellular zinc. But high dose zinc supplementation will produce deficiency of copper, and copper is a natural inhibitor of Furin. Many integrative physicians make the mistake of measuring zinc in red blood cells or whole blood to establish zinc status this is inaccurate, because intracellular zinc reflects the levels of zinc-containing proteins, which is not a guide to zinc deficiency or adequacy. Plasma zinc is much more meaningful. Inflammation leads to a sequestration of zinc in the liver, however, so in severe inflammatory states, plasma zinc also becomes an unreliable index of zinc status. Finally, dietary zinc supplementation increases the risk of bowel inflammation due to overgrowth of the pathogenic bacteria, Clostridum difficile. Dietary zinc increases toxin-production and virulence of C. difficile in laboratory animals and in humans. Hospitalization, especially when associated with the use of antibiotics or acid-suppressing drugs, is a major risk factor for C. difficile colitis. Zinc supplementation should not be used freely, but with caution.

Immune Modulation during Symptomatic Infection

The lung damage of advanced corona virus pneumonia is due to an overactive immune response, so some immune boosting therapies should be used only for prevention or early infection and not for severe illness. Fortunately, many of the substances already mentioned decrease inflammation and specifically down-regulate the NLRP3 inflammasome: resveratrol, luteolin, curcumin, andrographolides, and melatonin. There are many other dietary components that modulate NLRP3. Among these, black cumin seed (Nigella sativa and Nigella indica) has the most robust history of medicinal and clinical use. Their active ingredient is thymoquinone. Look for a product that specifies thymoquinone content (desirable is 5%). 

If you suffer from an autoimmune disease, it may not be advisable to use melatonin, mushrooms, elderberry, prebiotics or probiotics that stimulate innate immune function. If you become  sick with symptoms of COVID-19, you should stop the use of medicinal mushrooms elderberry and immune-enhancing pre- or probiotics.

The first step is to develop these habits: Wash your hands with soap and water for 20 seconds before eating, touching your face, after being with other people and when you return home. A face wash is also a good idea.  Soap is the ideal anti-coronavirus cleanser, because it destroys the virus’s protective envelope. Do not use antibacterial soap it will not kill viruses and will only damage your skin’s microbiome.

COVID-19 remains viable on surfaces like plastic and stainless steel for 48 hours, on cardboard for about 24 hours and on copper for 4 hours. The infectivity of the virus declines with time. After 6-7 hours on steel or plastic, half the particles have lost viability. The viral half-life on copper is under one hour. 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). The studies 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% alcohol and might be an adequate substitute for soap, but remember that contact needs to be maintained for 30 seconds. Clean door knobs, phones and keyboards daily or more often.

Microwave ovens can kill some strains of corona virus that contaminatie food. In the one study done, death occurred in 20 seconds. . For helpful information about handling food safely, view this YouTube video:

The use of face masks has become a major strategy in the government’s attempts to stop the spread of COVID-19. The CDC has recently reversed its advice that asymptomatic people should not wear face masks in public.  This is long overdue but has created a great deal of confusion: what type of mask? How effective is each kind? Is there a downside? A review of 34 studies found that simple masks, even homemade ones, have a significant protective effect on viral spread through communities.

Here are links to other articles that attempt to guide readers in making choices about masks:

Face masks aside, the old rules still apply: If you are sick, stay home and wear a surgical mask around other people. N95 respirators are fairly uncomfortable when worn for extended periods of time and should be reserved for health professionals. 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. Social distancing prevents viral spread try staying six feet away from other people, especially if you’re sick.

Various metals are being touted for their anti-viral effects. Do not fall for the hype. Copper and its alloys like bronze are the most potent of the anti-viral metals. However, several hours of copper exposure are needed to eliminate COVID-19, unlike cold viruses, which are killed in 60 seconds. Because the mechanisms by which different metals kill viruses tend to be similar, it is unlikely that metals like zinc or silver will be effective at killing COVID-19. Furthermore, the silver preparations tested in scientific studies are different from the colloidal silver that is sold in health food stores, so colloidal silver sprays cannot be relied upon for protection. High levels of zinc kill some corona viruses but are less effective than copper. Although some doctors advocate the use of zinc lozenges to prevent COVID-19, 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.

Ever since the SARS-CoV-1 epidemic, which lasted from 2002 to 2004, scientists have been searching for drugs (old and new) to improve the outcome of corona virus infection. There are two categories of established, readily available, FDA-approved drugs that are promising:

  1. Anti-parasitic drugs: The anti-malarials, chloroquine and hydroxycholoroquine (Plaquenil), have received the most attention. A research paper from China published last month demonstrated potent killing of COVID-19 by these drugs in laboratory studies, with hydroxychloroquine being superior. Plaquenil is generally used as an immune modulator for autoimmune diseases or as an enhancer of antibiotic effectiveness for infections like Lyme disease. It is typically taken for months or years at a time. In humans, Plaquenil has been shown to rapidly reduce the number of live COVID-9 particles the addition of the antibiotic azithromycin improved the Plaquenil response, so that there was no live virus left after 6 days. Clinical trials with Plaquenil and azithromycin are underway in the U.S. Both these drugs may cause life-threatening cardiac arrhythmias they must only be taken under medical supervision. Ivermectin, a drug for eradicating worms, has recently been shown to decrease the entry of SARS-CoV-2 into cells by a factor of 5000, with just one application. Ivermectin is inexpensive and has a high safety profile. It will undoubtedly be the subject of clinical trials. Nitazoxanide (Alinia), approved for treatment of the parasite Giardia lamblia, has been proposed as a useful add-on to Plaquenil. Alinia has anti-viral activity and also up-regulates anti-viral defenses by boosting Type 1 interferon production.
  2. The anti-malarials, chloroquine and hydroxycholoroquine (Plaquenil), have received the most attention. A research paper from China published last month demonstrated potent killing of COVID-19 by these drugs in laboratory studies, with hydroxychloroquine being superior. Plaquenil is generally used as an immune modulator for autoimmune diseases or as an enhancer of antibiotic effectiveness for infections like Lyme disease. It is typically taken for months or years at a time. In humans, Plaquenil has been shown to rapidly reduce the number of live COVID-9 particles the addition of the antibiotic azithromycin improved the Plaquenil response, so that there was no live virus left after 6 days. Clinical trials with Plaquenil and azithromycin are underway in the U.S. Both these drugs may cause life-threatening cardiac arrhythmias they must only be taken under medical supervision.
  3. Ivermectin, a drug for eradicating worms, has recently been shown to decrease the entry of SARS-CoV-2 into cells by a factor of 5000, with just one application. Ivermectin is inexpensive and has a high safety profile. It will undoubtedly be the subject of clinical trials.
  4. Nitazoxanide (Alinia), approved for treatment of the parasite Giardia lamblia, has been proposed as a useful add-on to Plaquenil. Alinia has anti-viral activity and also up-regulates anti-viral defenses by boosting Type 1 interferon production.
  1. Antihypertensives, a class called ARBs (angiotensin receptor blockers), which are normally used to reduce blood pressure and protect kidney function. ARBs increase ACE-2 activity and have been proposed as a treatment to promote healing of the lung in corona virus pneumonia. A recent study from China demonstrated through indirect measures that ACE-2 function declines with viral load and severity of COVID-19 pneumonia. For people already taking blood pressure medication, the inclusion of an ARB may improve the response to COVID-19 infection. The Federal government is sponsoring a trial of the ARB losartan for amelioration of COVID-19. However, the ARB that most enhances ACE-2 levels in humans is olmesartan (Benicar). Of all the ARBs, olmesartan has the greatest impact on immune function. One caveat: a rare but serious autoimmune complication of olmesartan has been described by the Mayo, severe diarrhea mimicking celiac disease and/or lymphocytic colitis.

There is misinformation circulating on the Internet that attributes a high death rate with COVID-19 to ARBs and another class of drugs called ACE inhibitors. This opinion is speculative and based on no evidence it reflects a faulty understanding of corona virus biology and the role of ACE-2 exhaustion in determining disease outcome. A recent study from China found no association between the use of ACE inhibitors or ARBs and severity of COVID-19.  


  1. Before symptoms begin: Enhance anti-viral immunity with vitamin D, prebiotics, probiotics, mushrooms (turkey tail or reishi), low dose melatonin, and elderberry Consume flavonoids and other plant-based polyphenols for 2 purposes Support ACE-2 activity Build up cellular levels to inhibit the action of 2 critical protease enzymes (Furin and 3CL-protease).
  2. Enhance anti-viral immunity with vitamin D, prebiotics, probiotics, mushrooms (turkey tail or reishi), low dose melatonin, and elderberry
  3. Consume flavonoids and other plant-based polyphenols for 2 purposes Support ACE-2 activity Build up cellular levels to inhibit the action of 2 critical protease enzymes (Furin and 3CL-protease).
  4. Support ACE-2 activity
  5. Build up cellular levels to inhibit the action of 2 critical protease enzymes (Furin and 3CL-protease).

Substances include curcumin, luteolin, resveratrol, quercetin, Andrographis, and elderberry. Ground flax seed and black tea may also be helpful.

  1. If symptoms have already started, or once symptoms begin, do not take elderberry, mushrooms, prebiotics, or probiotics, unless advised to by a knowledgeable health care provider. Continue to use or begin taking curcumin, luteolin, resveratrol, quercetin, melatonin and Andrographis. Add thymoquinone (from black cumin seed) and Houttuynia cordata, if available.
  2. If symptoms are severe or if they do not improve within 3 days, you must consult a medical professional.



  1. Quinlan

    Very funny answer

  2. Mikak

    Thanks a lot! I have been looking for it in good quality for so long.

  3. Alwin

    judging by the rating, you can take

  4. Fenrijora

    It is very welcome.

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