Biological Theories

An Evolutionary Biological Take on Long Covid

There are several biological theories for Long Covid. While some might argue that the biology doesn’t matter because there is no gold standard biological test or treatment, a primary concern for patients is the legitimacy of their symptoms that is confirmed through understanding what the heck is behind their ill-health. That is why people like Ty have spent thousands of dollars to figure out how their body is dysregulated in order to figure out any possible treatment. What’s difficult is that we remain far away from understanding what can be done for people living with Long Covid and other conditions like myalgic encephalomyelitis (ME). As I move forward, I’m dropping the use of ME/CFS because I’ve been instructed by ME activists that using the CFS construction is demeaning in the patient community because it reflects a history of dismissive medical care, where fatigue overshadows the complexities and myriad symptomatologies of their conditions. An alternative has been suggested: systemic exertion intolerance disease.

I spoke recently with Dr. Anthony Komaroff, a physician and professor at Harvard Medical School and Brigham and Women's Hospital who has studied ME for the past several decades. Like Fauci, Dr. Komaroff started studying ME in the 1980’s, just as the AIDS pandemic was beginning. Although it was clear that AIDS was a “real” disease—it had specific and unusual objective abnormalities such as purple-colored spots on the skin and unusual parasites infecting the lungs, and it led to wasting and death—at first there were no clear objective abnormalities with ME.  This caused people to disappear into their private, internal worlds at home to tend to an illness that many people describe as “invisible” because the dysregulation of the body takes down multiple internal systems at once. This is one reason many ME activists lose steam for a visible life in activism, advocacy, or, in many cases, work. ME activist and director of advocacy for the Minnesota ME/CFS Alliance told me that many people he works with prefer to direct their spoons to nurturing their loved ones and their family lives, rather than pouring their limited energy into politics they don’t think will change much. In doing so, many people reorient their identities, social roles, and lives and redefine life priorities and meaning in the face of illness.

Unsplash: free to use, Scott Webb

Back to Komaroff. In the early 1980s, Dr. Komaroff met several patients with an acute illness that was followed by years lingering symptoms. He knew it wasn’t AIDS—there was a test for that. They set up research protocols and compared notes around the country. With financial support from the National Institutes of Health, he and others were awarded grants to study ME. Since ME is an illness that involves many different organs, NIH support for research on ME comes from several different Institutes (such as the Institutes dedicated to brain diseases and infectious diseases).

While in the 1980’s and well into the 1990’s there was little evidence of underlying biological abnormalities in ME, Komaroff says that has changed greatly in the past 25 years. It now is clear that there are abnormalities involving the brain, immune system, energy metabolism, blood vessels, heart and lungs and the bacteria that live in the intestines. Furthermore, over the past two years, it is becoming clear that many of these same abnormalities are seen in people with Long COVID.

Komaroff has argued that there are two central questions for people living with Long Covid. First, what is triggering these symptoms to have abnormalities? Second, do any of these abnormalities affect, and worsen, each other, triggering vicious cycles?  If this is the case—if abnormalities in one system generate or worsen abnormalities in another system—then it can lead to reinforcing abnormalities that keep going for years.

With four decades of research under his belt, Komaroff explained to me an evolutionary theory for thinking about Long Covid that I found plausible and useful to think with. Let me explain, drawing on his clear explanations. First, he explained, you've had the flu. You know how you feel when you get the flu and the symptoms you get. Why, when an infectious agent enters your body, do you begin to feel sick? Why do you have achiness, fatigue, difficulty concentrating, loss of appetite, reduced interest in sex, an increased need to sleep and other symptoms?

This feeling isn’t only a human experience. Instead, it also affects animals when they get sick. It’s called “sickness behavior”, and he says it is seen in virtually “all animals—even worms and fruit flies. Following an infection, their behavior changes. They act like we act like when we get sick. In other words, this change in behavior following infection has been preserved by evolution over hundreds of millions of years.  That raises an obvious question: why?  Why would nature have created sickness behavior following an infection?”

Komaroff says that “the theoretical reason that nature causes this behavior when a person or an animal is infected is that the behavior change reduces energy-consuming activities.  It takes energy—molecules of ATP—to move, to think, to digest food, to have sex, and so on.  And your body needs all the energy it can get to fight the infection.”

Unsplash: free to use, Riccardo Annandale

If this theory is right, if infection leads to sickness symptoms, which then cause sickness behavior, which saves the energy the body needs to fight the infection, then the next question is how are the sickness symptoms created?  To scientists, that is an important question because if the mechanisms in the body that lead to a disease, or to the symptoms of a disease, are understood, then you have a better chance of finding cures that work by altering those mechanisms.

Komaroff’s theory as to how sickness symptoms are caused is as follows: “Symptoms are experienced in the brain. We already know that the brain is full of what are called ‘nuclei’—groups of brain cells (neurons) dedicated to particular tasks—like seeing light that enters the eyes. At least in rodents, there are specific nuclei in our brains that are dedicated to causing sickness symptoms: fatigue, loss of appetite, achiness, diminished sex drive, difficulty concentrating. It is likely that similar nuclei exist in humans, causing these symptoms in us. These “sickness symptoms” then lead to “sickness behavior”: we stop moving around, eating, or doing anything that requires energy. The energy molecules, ATP, that we would have used to be physically and mentally active are now freed up to fight the infection.”

While this made sense to me, I asked Dr. Komaroff why does this become permanent for some people? He responded that there are two possibilities. The first is that there is a switch in the brain that turns on this sickness behavior—and it gets stuck in the “on” position. Normally it should be turned off, like when you fight off the flu, you are no longer fatigued and go back to normal. However, it’s possible that the switch gets stuck in ME. The other possibility is that the sickness symptoms are not turned off because, in fact, the infection that triggered them remains.  “In Long Covid, for example” he explained, “I have come to think that what’s happening with most people is the virus is not fully gone – it hangs around in the body. Possibly the full living virus, still capable of reproducing itself. Surely, pieces of the virus. The immune system sees these pieces and tries unsuccessfully to eradicate them. As long as this low-grade immune system attack on the remnants of the virus continues, the sickness symptoms persist.”

I nodded, thinking about the work by PolyBio that I have found so instructive, arguing that the virus attaches to the vagal nerves and tricks the body into thinking its sick.  Komaroff argued, reflecting on the work of PolyBio:

“We know for sure that Mike's hypothesis in particular, was that the cells that run along the spinal cord themselves become infected and lead to these signals up the vagus nerve to the brain. And I think that's entirely plausible. But it doesn't need to be these cells. If you just have inflammation anywhere in the body--particularly in the gut—this sends signals up the vagal nerve to the brain. These signals from the gut then activate the brain’s immune system to prepare the brain to deal with a possible infection.

I asked: do these warning signals also travel in the blood? Dr. Komaroff responded:

“Certain inflammatory molecules travel in the blood. What I was taught in medical school was that there is a barrier between the blood and the brain, and that inflammatory molecules that travel through the blood cannot get through that barrier to get to the brain. However, for 15 years it's been clear that's simply not true: there are certain areas in the brain where that barrier is tattered and where molecules can easily get through. It's also true that when there's inflammation in the body, the inflammation makes the barrier become porous and makes it much easier for those inflammatory molecules to leave the blood and go into the brain.”

I was intrigued and followed up with more direct questions about the processes of neuroinflammation.

“Neuroinflammation means that the innate immune system of the brain has been activated. This can happen because there's an infectious agent inside the brain, or because there's inflammation somewhere else in the body like the gut that is sending signals up the vagus nerve and through the blood to the brain. Neuroinflammation, in turn, generates the creation of inflammatory molecules (like cytokines). These molecules then triggers these nuclei to generate the symptoms of the illness.“

So after 40 years of studying this? What do you think is the best in intervention? An antiviral? Something else? Komaroff responded:

“No, not an antiviral. Without evidence that a specific virus is involved, an antiviral wouldn’t work [especially if there are multiple co-existing viruses working together.] I don't believe this illness is like HIV/AIDS. I don't believe this is an illness caused by a single novel infectious agent where a cure would involve an antiviral against that agent. I think this is an illness that can be triggered by multiple infectious agents (certain viruses,  bacteria and  parasites) and possibly also by major physical injury or trauma.”

Instead, he thinks effective treatments are more likely to come from targeting the neuroinflammation. He explained,

“So having told you what my theory of the illness is, if the final common pathway leading to the symptoms of the illness are those nuclei in the brain that are causing the symptoms and that are stimulated by neuroinflammation, then the best treatment is likely to prove something that quells neuroinflammation and ideally, specifically acts on those nuclei to keep them from being triggered from neuroinflammation. But we’re just at the beginning. The nuclei themselves were just discovered within the last couple of years. I think the people who discovered them probably now are studying in detail what the chemical signals are that turn those nuclei on and how to block those signals. So maybe within the next 5 years we'll begin to have some answers that apply in rats and that might just work in humans.”

There are some drugs that are proving effective in rodents at mitigating the processes he suggests:

“There are certainly drugs that can counter the effects of cytokines and other inflammatory molecules like eicosanoids. Drugs that can block the inflammatory molecules and that also can reach the brain—that can get through that barrier into the brain that I mentioned—might prove to be effective treatments.”

Finally, I have been curious if Long Covid is associated with other neurological conditions like Alzheimer’s or Parkinson's. “There’s already evidence that people who have developed acute COVID-19—even some who were only mildly ill—may be more likely to develop dementia in the next several years following “recovery” from acute COVID-19.  COVID-19 causes neuroinflammation. There now is growing evidence that neuroinflammation plays an important role in neurodegenerative diseases, including Alzheimer's disease. So, unfortunately, it is plausible that COVID-19 may increase the risk of neurodegenerative diseases.” 

Our conversation went on for more than an hour, but I’ll leave our discussion here. Dr. Komaroff ended with these comments, “The only way I know to cure a disease is to understand what is going wrong in the body that leads to the symptoms of the disease.  For nearly 30 years, not enough effort was made to understand the things that are going wrong in the body in people with ME.  I’m encouraged by the increased interest over the past decade, and by the large effort to understand Long COVID.  I think it is likely that what is learned about the body’s abnormalities in ME/CFS often will prove applicable to Long COVID, and vice versa.”