Scientists Solve the Long-unsolved Mystery: How Lengthy Covid Studies Could Help Solve Post-viral Sickness Problem?

Large infectious disease epidemics frequently leave a small fraction of people with a particular constellation of disabling symptoms that persist long after the primary illness has run its course, as scientists and doctors have known for at least a century.

They haven’t been able to explain why, and many people are now hopeful that the current covid pandemic will assist them to do so.

An estimated 4 million Americans are unemployed as a result of long-term disease, and more than 23 million are likely to have their quality of life significantly reduced. Covid survivors are more likely to have cardiac issues, blood clots, diabetes, and dementia, according to studies. The pandemic presents a bleak opportunity for understanding why some illnesses result in chronic illness and finding medicines that might benefit more than simply lengthy covid, with the National Institutes of Health devoting more than $1 billion to research on covid’s long-term impacts.

According to Anthony Komaroff, a professor and physician at Harvard Medical School, “if we can catch people at the outset of their covid, and then examine the people who do go on to develop extended covid, we’re in a better position to understand the underlying biology.” “However, it’s not a given that the lessons learnt from Long Covid will hold for other post-infectious fatigue syndromes brought on by different infectious agents. However, I’m betting that it will because everything here is a component of a broader picture.

There are many other situations included in that bigger picture. Epidemiologists found that many survivors of the 1918–1919 influenza pandemic, which sickened 500 million people globally, had a two-three times higher risk of developing Parkinson’s disease than persons who were born at different eras. Additionally, a study released earlier this year found that the Epstein-Barr virus, which affects billions of people globally, increases the risk of multiple sclerosis by a factor of 32.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a crippling illness that affects as many as 2.5 million Americans and is marked by an extreme weariness that frequently gets worse with exercise, may be brought on by the same virus. Since at least the 1980s, isolated cases of ME/CFS have raised the possibility that an infection may be the cause of the condition, which has several symptoms in common with long-term covid.

Before covid, a relatively tiny group of underfunded academics had been working hard to comprehend these disorders, which many in the medical world had written off as psychosomatic. However, many questions remain unresolved.

Scientists are now prepared to respond to important concerns, such as how frequently such illnesses follow an infection or whether there are risk factors, thanks to the attention, money, and oversupply of study participants covid has generated. Researchers may discover how viruses can cause some immune systems to go into chronic overdrive and whether persistent symptoms are caused by viruses hiding out in difficult-to-reach tissues. Researchers may create novel medicines that benefit more than only long-covid patients if the bigger picture becomes clear.

Success is by no means assured. It is risky to assume that the lessons acquired from researching the impacts of long covid will apply to other conditions because long covid is probably not one thing but several. The University of WĂĽrzburg’s Bhupesh Prusty, a molecular virologist, noted that there was still much to learn.

We have a rare chance to use extended Covid as a model system to comprehend how a widespread viral infection might lead to post-viral sickness later on if all post-viral illnesses have the same symptoms, and why some people get these illnesses while others fully recover, he said. “These are such crucial concerns that have been ignored for far too long.”

Lingering virus, lingering problems

The fact that viruses never go away may be the simplest explanation for why symptoms persist long after the primary disease has subsided.

Viral holdovers are the cause of some of the most prevalent diseases. Years after the virus first caused chickenpox, varicella-zoster reactivates to produce shingles. When specific herpes virus strains act up, cold sores appear. Viral encampments in joints and eye tissue, which have both been seen, could cause joint discomfort after chikungunya infection or visual issues after Ebola.

People believe in post-viral syndromes; it’s not a new idea; they simply don’t think of it that way, according to Jarred Younger, a neuroscientist at the University of Alabama in Birmingham.

According to Komaroff, for more puzzling illnesses like long-term covid or ME/CFS, the triggering agent or bits of the agent, proteins that the agent has generated, somehow stay, lurking in privileged harbours someplace in the body, even when the acute illness appears to have subsided. Since it hasn’t been eliminated, the immune system is constantly pushed because of it.

A person may experience symptoms of illness even after the virus no longer manifests in routine testing, such as a blood or nose swab, due to this persistent prodding of the body into a condition of chronic inflammation.

It has been difficult to identify those residual viral particles or debris and to demonstrate that they are the cause of a variety of symptoms. As a virologist at Johns Hopkins University, Diane Griffin stated, “It’s one thing to have a brain infection and see apparent deterioration linked with that, but it’s quite another thing to feel exhausted and just not back to normal and try to determine how a lingering virus may be doing that.”

That’s particularly difficult in cases like ME/CFS where it’s not even clear what virus to look for.

Since there have been multiple outbreaks of chronic fatigue syndrome and many sufferers can link their symptoms to infection, researchers investigating the ailment have long suspected a viral cause (or causes). However, without knowing what the pathogen is, it is difficult to say whether it is still present in the body. Additionally, it is challenging to search for viruses in organs like the brain where they may be most important. Griffin added, “It’s difficult to do this without obtaining a bit of the brain and examining to see if the virus is there or not, and that always comes with some danger.”

After an acute infection, a virus that has persisted in the body, particularly in the brain or neurological system, “may make you feel extremely miserable,” the doctor said. “The information has not been available to establish that connection. But that does not imply that it is nonexistent.

Enter long covid

The reason why long covid is unique is that researchers are aware of what they are looking for and know where to seek it. According to a recent autopsy investigation, SARS-CoV-2 genetic material has been discovered throughout the body, including the gut, heart, and brain. Griffin added, “I think the most plausible explanation for extended covid is perseverance.

Scientists Solve the Long-unsolved Mystery

Another benefit for scientists researching the long-term impacts of COVID is that many patients with extended COVID are aware of the time of their infection, which enables researchers to compare them with those who don’t experience these issues to those who do. With other illnesses like ME/CFS or post-viral Parkinson’s, when patients might not have given a routine infection much thought, that hasn’t been possible on a large scale.

But demonstrating cause and effect come with its difficulties. It’s one thing, according to Debby van Riel, a virologist at Erasmus University in Rotterdam, Netherlands, “when you can look under a microscope and observe cells dying and evidence of inflammation around viral antigens during the acute phase of infection.” It will need more than just discovering the virus scattered throughout the body to prove that it is the source of long-term covid, the expert said.

Dousing the body with antiviral medications may be useful if such reservoirs are shown to be connected to symptoms that last for a long time. Griffin explained, “Right now, we’re looking at how much antiviral usage affects the persistence of RNA in monkeys. Future generations of antivirals may prove effective, possibly also for other viruses, even though the current crop isn’t great and hasn’t been thoroughly investigated.

According to Michael VanElzakker, a neuroscientist at Massachusetts General Hospital and Harvard Medical School, “We need an Operation Warp Speed or Moonshot for antivirals.” Increasing the effectiveness of our antiviral arsenal, he said, might significantly lessen suffering if even a small portion of post-infection syndrome symptoms are caused by persistent viruses. Antiviral medications still in development can benefit certain ME/CFS patients, but more study and development are required. VanElzakker remarked, “If we truly pushed antivirals, it could make a tremendous difference.

Viral Hit And Runs

However, infections don’t need to linger to cause persistent issues.

An infection usually triggers the immune system to launch a flurry of activity meant to overwhelm the intruder. Part of what sickens us about that deluge of activity is that it finally reaches its height and the blizzard dissipates into a few flurries. However, infections tend to interfere with this normal rhythm in certain people. The immune system can become chronically overactive in certain areas. The immunological blizzard either never completely ceases or becomes too easily triggered even after the pathogen has vanished.

According to Maureen Hanson, a molecular biologist at Cornell University, “the assumption is that some immune systems that got ratcheted up to deal with a viral infection never quiet down.” Because it reacts as if a virus is there even when there isn’t, it becomes dysregulated and makes people feel unwell.

Some immune cells may experience exhaustion due to this state of overactivation. Natural killer T cells, a type of white blood cell that aids in the initiation of an immune response, become much less active in persons with ME/CFS. When these cells run out of energy, hidden viruses that probably weren’t the cause of the initial dysregulation—such persistent viruses as herpes viruses—spring back into play.

According to Liisa Selin, an immunologist at the University of Massachusetts Medical School, “it appears that this level of tiredness causes the reactivation of a number of the chronic viruses in our body, particularly herpes viruses.” This reactivation has the potential to overload an already compromised immune system, leading to a variety of symptoms, including the death of brain cells, and aggravating dysregulation. According to preliminary research, long-covid patients exhibit comparable symptoms of latent viral reactivation.

Scientists are yet unsure of the causes of dysregulation or reactivation, as well as whether any risk factors make some immune systems more susceptible to malfunction. Researchers may be able to observe these processes in action and search for genes or environmental elements that may be linked to long covid and possibly other conditions by studying long covid.

Many of the neurological symptoms that can appear after infection may be brought on by chronic inflammation of the immune cells in the brain (known as microglia), which can be stoked by overactive immune systems, according to Younger. According to him, some viruses may be traumatising or sensitising microglia, leading the cells to remain hypersensitive. “The person will feel sick as a result of constantly being on alert.”

Postural orthostatic tachycardia syndrome, or POTS, which affects the operation of involuntary systems including heart rate, respiration, and body temperature, may also be a factor in other illnesses connected to post-infection weariness.

Richard Smeyne, a neuroscientist at Thomas Jefferson University who researches the long-term consequences of influenza, said that such hypersensitivity may also be the cause of the higher risk of Parkinson’s after influenza infection. The viral infection is sensitising the nervous system to other insults, which will happen later, including other pathogens or environmental toxins, he said, suggesting that the flu itself may not be the cause of this. “Any one of them by themselves wouldn’t cause the disease to spread, but when you mix them, they have a synergistic effect on one another.”

According to Smeyne, any increase in Parkinson’s disease brought on by SARS-CoV-2 would take decades to show up, but the pandemic might help researchers finally identify risk factors for this form of sensitization. “By infecting millions and millions of people with covid, nature has given us the first half of the experiment,” he stated.

According to him, over time, researchers may be able to determine if those who were exposed to more agricultural chemicals or those who contracted SARS-CoV-2 more than once had a higher risk of getting Parkinson’s disease or other neurological problems.

A Tragedy — and an Opportunity

There are probably a lot more ways than these for viral infections to result in chronic illness. When viruses utilise human cells to replicate, they can sometimes cause actual harm to tissues. In the case of long covid, microscopic blood clots caused by the coronavirus spike protein may be causing cellular havoc. A virus may impair a cell’s capacity to make and use energy, upset the balance of the gut microbiota, or lead the immune system to mistake healthy tissues in the body for foreign invaders, triggering the onset of an autoimmune illness.

Understanding lengthy covid and other SARS-CoV-2 problems will only partially complete the picture because it’s likely that several of these elements interact with one another to generate post-viral disorders. It will take paying attention to all of these patients, involving them in the research process, and building on prior knowledge to ensure that the NIH’s billion-dollar investment in long covid research results in relief for patients suffering from long covid and possibly other post-viral illnesses as well.

According to Hannah Wei, a co-founder of Patient-Led Research Collaborative, a group of long-term patients who are also researchers, “the lowest-hanging fruit is to ask patients what their objectives are at the beginning of the research.” That not only directs research into potential remedies, but it also suggests research issues researchers would not have considered.

One of the main symptoms of ME/CFS, post-exertional malaise, was described by the patient community, according to Komaroff, who was involved in early studies on the illness. Patients brought it up to the doctors’ notice since “no doctor would have ever thought to inquire whether you feel ill the day after exerting yourself physically or mentally.” That aided in directing research that revealed important physiological variations in how ME/CFS individuals react to exercise.

It’s also critical to realise that researchers looking into the long-term effects of COVID aren’t beginning from blank. Long-term disease research, according to Jaime Seltzer, head of scientific and medical outreach at advocacy group MEAction, “is still catching up to ME/CFS research.” We are repeatedly verifying findings from smaller [study] cohorts that were brought on by different virus infections, the researcher said. According to Seltzer, pre-covid research into post-viral disorders was underfunded, had smaller sample sizes, and flat-out discounted the reality of these conditions.

With covid, all of that has changed. Previously doubtful physicians or researchers may now have long-covid sufferers among their colleagues or be one themselves. Long-term care research is receiving financing that past researchers could only dream of, and studies are finding patients much more readily.

Adriane Tillman, an editor at MEAction who has ME/CFS, said, “We really can’t let this go to waste.” It’s a great tragedy, but it also presents a great opportunity.

Stay tuned for more updates, and

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