Are There Biomarkers for Long COVID?

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A Q&A With Patrick Hanaway, MD  •  A Q&A With Jacob Teitelbaum, MD

Long COVID is real. Once viewed with skepticism as a sort of phantom or, at best, psychosomatic disease, its blood biomarkers have now been pinpointed, and immuno­phenotyping tests are 96 percent accurate in its identification.

This not only establishes the legitimacy of long COVID, but it may lead to new treatments. That’s the conclusion of researchers from the Icahn School of Medicine at Mount Sinai and Yale School of Medicine in a study published last year in Nature.

“These findings are important — they can inform more sensitive testing for long-COVID patients and personalized treatments for long COVID that have, until now, not had a proven scientific rationale,” said co-principal investigator David Putrino, PhD.

Still, while data now confirms the reality of long COVID, the condition remains a puzzling challenge for researchers and patients alike.

PostViral Fatigue

Long COVID is a postviral syndrome, explains functional-medicine practitioner Patrick Hanaway, MD. It’s closely related to myalgic ­encephalomyelitis/chronic fatigue syndrome. And a similar wave of postviral syndrome occurred following the 1918 Spanish flu pandemic, he says.

Integrative-medicine internist Jacob Teitelbaum, MD, describes how a postviral syndrome develops: “Many infections do not have the mitochondrial ‘machinery’ needed to produce their own energy. Rather, they hijack our body’s energy production to reproduce. Our body suppresses our own energy production to starve the viruses. This is one reason people feel tired during many severe viral infections.”

After recovering from COVID, an ­estimated 10 percent of people still suffer from suppressed energy production, he says. “This then triggers a chain reaction in the body with hypothalamic dysfunction, widespread muscle shortening and pain, and a form of inflammation in the brain called microglial activation. Each of these then triggers its own cascade of events. Immune activation and exhaustion occur alongside the low energy — likely two sides of the same coin.”

The Future of Long COVID

Long COVID has proven especially confusing because it features more than 200 possible symptoms, ­Hanaway says — two of the most common being brain fog and post-­exertional fatigue. “There’s no one thing going on here. . . . There’s a convergence of factors.”

And new findings on long ­COVID keep emerging: A recent study pub­lished in Cell found that sufferers have lower serotonin levels, presumably triggered by remnants of the virus lingering in the gut. The authors state that depleted serotonin could trigger neurological and cognitive symptoms, including memory issues.

1 in 10:  Estimated number of people with COVID who subsequently developed long COVID — including up to 23 million Americans, reports the National Institutes of Health.

Long COVID can strike anyone, Hanaway notes. “A third of the people with long COVID had no other health issues beforehand. None. So, it isn’t just the obese, the diabetics, the elderly who are getting it. This is actually across the whole spectrum.”

Equally concerning, he says, is that every time you contract a COVID infection, it increases your likelihood of getting long COVID.

Overcoming COVID once doesn’t seem to be protective, he explains: “That’s scary. Many people who weren’t sick are getting sick, and you’re more likely to get long COVID if you get COVID again.”

There are studies, meanwhile, suggesting vaccination lowers the likelihood of developing long COVID, though it doesn’t eliminate it. And the number of people reporting long-COVID symptoms has declined since June 2022, suggesting its symptoms may eventually resolve for many people — though it takes longer than anyone would like.

(For a report on long-COVID treatments, see “How to Treat Long-Haul COVID.”)

A Q&A With Patrick Hanaway, MD

“The epidemic of COVID is one thing, but the pandemic of long COVID is having a much more serious impact on our healthcare system,” says functional-medicine practitioner Patrick Hanaway, MD. Long COVID strikes an estimated 10 percent of people who get COVID and its price is a heavy toll; Hanaway notes that Harvard economist David Cutler, PhD, has estimated the total cost of long COVID will be $3.7 trillion in healthcare, lost wages, and quality of life.

Hanaway is working with a group of fellow physicians on treatments for long COVID, but simply understanding the genesis and ramifications of the disease has been the first great hurdle.

We spoke with Hanaway about how long COVID develops and affects our bodies.

Experience Life | There is an array of different explanations for long COVID, but they all seem to come down to this concept of it being a postviral syndrome. Can you explain what a postviral syndrome is?

Patrick Hanaway | What we’ve learned is that, after a viral infection, there are long-term changes that can occur. We first began to really recognize this in the [19]80s with the emergence of myalgic encephalomyelitis, or chronic fatigue syndrome. And when we go back and start looking, we actually find one of the biggest times this happened was following the Spanish flu epidemic that occurred at the end of World War I. Today, this is clearly seen with the SARS-CoV-2 virus. And those of us in the functional-medicine arena began to see this begin literally two months after the first infections were emerging.

EL | How does the identification of long-COVID blood biomarkers help?

PH | The biomarkers form a validation that there is a consistency of a pattern of what is referred to as the immune phenotype — that’s what’s happening with the immune system and various immune markers in the patients who have these more than 200 different symptoms of long COVID.

EL | Does finding the blood biomarkers actually direct treatment?

PH | No. The gut microbiome produces less serotonin, affecting the brain and decreasing stimulation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to a decrease in cortisol production. And we know that there are imbalances in the immune system, but we don’t have specific remedies for those findings. And it also doesn’t tell us what’s the mechanism of why that’s happening. There is no one thing that’s going on here; there’s a convergence of factors. We think there are five primary drivers of long COVID:

1. ACE2 receptor damage and microclots
2. Chronic persistent inflammation
3. Viral persistence
4. Microbiome dysbiosis
5. Mitochondrial dysfunction

We know that when the virus binds to the cells, they bind at the ACE2 receptor, and there can be damage that happens where that binding occurs. So that’s the first thing.

We know that there’s acute inflammation that becomes chronic inflammation in these patients. That chronic inflammation would be represented by the immunophenotyping blood markers.

[We’re] finding is that there are fragments of virus. It’s not necessarily a whole virus, but we do know that viruses can hide and get sequestered in our bodies.

Now, there’s a question about the chronic inflammation: Is it possible that some of these people still have the virus? And what we’re finding is that there are fragments of virus. It’s not necessarily a whole virus, but we do know that viruses can hide and get sequestered in our bodies. A classic example of that would be the chickenpox virus, which is called varicella. After we are young and we have chickenpox, the varicella-zoster virus goes into the dorsal nerve roots along our spinal cord and can come out as shingles when we are immunologically weakened. There are other viruses where this can happen, like herpes simplex, human herpes virus 6, Epstein–Barr, and many other viruses. So, this is not uncommon at all.

The initial infection can affect some people’s lungs [or] some people’s heart, and [cause] inflammation of the myocardium. In some patients, it causes changes in their brain, causing brain fog or mood disorders.

We also find that there’s a signature of an alteration of the microbiome, and that people whose gut microbiomes had been altered were more likely to get long COVID. People who have long COVID have a specific signature of alterations in their microbiome. And we know that the microbiome is closely related to the immune system. There’s actually a triad of interaction because both the microbiome and immune system communicate closely with the mitochondria.

The mitochondria produce energy. From a functional-medicine perspective, when we see issues of brain fog and postexertional fatigue, which are two of the most common symptoms in long COVID, those symptoms generally derive from poor energy production, which happens in mitochondria. Suffice it to say that the brain uses more energy, ATP [adenosine triphosphate], than any other part of our body. When we exercise and we have a higher demand for ATP for energy, that can cause the system to crash afterwards. And that’s what we see with a lot of these patients: brain fog and postexertional fatigue.

EL | And how is this focusing treatments?

PH | The interesting part of this is that there’s such a broad array of different symptoms that people have that one has to take a much more comprehensive approach to treat and work with it. We know that immunologically, there’s an issue because of the relationship of what’s going on with the brain — that the body doesn’t have the same capacity to deal with stress.

Thus, the idea is to take a multisystem or multipronged approach to treat it. We don’t have it dialed yet. We hoped we could find, “Oh, there’s five or eight different subtypes. And for this subtype we do this, and for this subtype we do that.” We would love to have that, but we’re not seeing that.

We don’t have it dialed yet. We hoped we could find, “Oh, there’s five or eight different subtypes. And for this subtype we do this, and for this subtype we do that.” We would love to have that, but we’re not seeing that.

There’ve been some retrospective reviews and papers that say there’s four or six subtypes, but there’s a lot of overlap between them. So, from a practicing doctor’s perspective, it’s not very helpful; it doesn’t really guide treatment at this point in time. But many of the kinds of studies that are being done are trying to take a single agent, like the antiviral Paxlovid, and say, ‘Hey, let’s give this a try and see if we are able to resolve it.’ And if it’s able to help 20 percent of the people, but 80 percent aren’t getting better, you’re not actually going to see benefit in a clinical trial.

But that’s just statistics. If you were able to figure out the 20 percent that were having the issue with viral persistence and you gave them the Paxlovid, maybe you would be able to see that effect. But we cannot yet define that subtype.

EL | What else are we learning about long COVID?

PH | One thing is that the significant majority of people who have had long COVID had only a mild initial COVID illness. So, we know that if you had a severe illness, you’re more likely to have long COVID. But because more than 200 million Americans have had this infection, there’s a lot of people with long COVID. So, there’s two other pieces that are important here.

One is that a third of the people with long COVID had no other health issues beforehand. None. So, it isn’t just people with obesity or diabetes or the elderly who are getting it. This is actually occurring across the whole spectrum of the population. We’re seeing the loss of work, the loss of productivity, to be huge.

The other thing is that if you’ve had COVID and you did not get long COVID, having another infection increases your likelihood of getting long COVID. More infections, more long COVID. It’s not as if it is protective. That’s scary. Many people who weren’t sick are getting sick, and you’re more likely to get long COVID if you get COVID again.

We’re in this current wave [in fall 2023 and early winter 2024] where there’s a new strain and more people are getting acute COVID infection. Thus, we have to really work vigilantly to understand and take a multisystem treatment approach.

EL | What are elements of treatment?

PH | This is foundational: In order for a multisystem treatment to work, you have to help people first to be eating a good diet. That nutritional foundation — if they’re eating “crappy food,” they cannot get better.

EL | And does exercise play a role as well?

PH | Exercise is an interesting one. Small amounts of targeted exercise are good, but if you overdo it, it’s bad. We know that exercise actually increases the efficiency of the mitochondria and energy production. But one of the hallmarks of this disease, of this illness, is postexertional fatigue. You push yourself too hard and you’re wiped out for a couple of days. So, the exercise prescription has to be judicious.

A Q&A With Jacob Teitelbaum, MD

Long COVID strikes an estimated 10 percent of people who get COVID and its effects can be devastating, resulting in fatigue, insomnia, cognitive dysfunction or brain fog, chronic pain, and more, says integrative-medicine internist Jacob Teitelbaum, MD.

He brings a unique perspective to the search for treatments. “In 1975, a nasty viral infection left me homeless and having to drop out of medical school for a year, when it triggered postviral chronic fatigue syndrome [CFS],” Teitelbaum says. “In learning how to recover myself, it helped in my developing a more comprehensive approach and understanding.”

Since then, he’s been focusing on effective treatments for postviral infections and other causes of CFS and fibromyalgia — which are related to long COVID.

“There are likely multiple, potentially overlapping, causes of long COVID,” notes a review published in Nature Reviews Microbiology of 210 studies. Several hypotheses for its pathogenesis are being examined, including persisting reservoirs of the virus in tissues; immune dysregulation potentially with reactivation of underlying pathogens, such as Epstein–Barr virus, among others; impact on the microbiota; autoimmunity; microvascular blood clotting; and dysfunctional signaling in the brainstem and/or vagus nerve.

Long-COVID symptoms are myriad. As a 2023 Mayo Clinic report notes, “Distinguishing PCC [postCOVID condition, another term for long COVID] from other conditions can be challenging because patients with PCC often report numerous and vague systemic symptoms.”

We talked with Teitelbaum about emerging treatments for long COVID.

Experience Life | Can you explain how long COVID develops after the initial COVID infection?

Jacob Teitelbaum | Many infections do not have the mitochondrial ‘machinery’ needed to produce their own energy. Rather, they hijack our body’s energy production to reproduce. Our body suppresses our own energy production to starve the viruses. This is one reason people feel tired during many severe viral infections.

Normally, after the infection passes, energy production returns to normal. But not always. In about 10 percent of people after COVID, energy production stays suppressed. This then triggers a chain reaction in the body with hypothalamic dysfunction, widespread muscle shortening and pain, and a form of inflammation in the brain called microglial activation. Each of these then triggers its own cascade of events. Immune activation and exhaustion occur alongside the low energy, likely two sides of the same coin.

The body shuts down energy production to starve the virus and is unable to turn energy production back on. So multiple systems start to fail.

So that is a moderately complex way of stating what occurs. In simpler English? The body shuts down energy production to starve the virus and is unable to turn energy production back on. So multiple systems start to fail.

In most people, long COVID begins with the initial viral infection. The fatigue simply doesn’t go away but instead progresses to the rest of the symptom complex after several weeks. But in some cases, people do recover for a few weeks to months, and then the symptoms come back after initially recovering.

EL | How is long COVID related to postviral chronic fatigue syndrome?

JT | For most researchers who are experienced in the field, long COVID and postviral chronic fatigue syndrome are the same thing. The research is also confirming this. Even Dr. [Anthony] Fauci recognized this early in the COVID epidemic.

EL | You have done multiple studies on treatments for CFS and fibromyalgia and written several books on the subject, including From Fatigued to Fantastic! and The Fatigue and Fibromyalgia Solution. How can these treatments help people recover from long COVID?

JT | Basically, our research focuses on increasing cellular energy production. For example, the molecule ribose is the backbone of energy production (ribose plus phosphate plus B vitamins are essential components of ATP, NADH [nicotinamide adenine dinucleotide], and the other key energy molecules). Research showed that ribose levels became deficient in CFS and fibromyalgia. So, we published two studies, one of which showed a 61 percent average increase in energy by simply giving the ribose.

We have also studied other herbs (for example, HRG 80 red ginseng) and nutrients (ribose in combination with licorice to help adrenal function), some of which showed quite significant benefit.

Though helpful, this is not enough by itself.

Our randomized double-blind, placebo-controlled published study showed that people do best using a comprehensive approach to increasing energy. Called the SHINE Protocol, it optimizes Sleep, Hormones/Hypotension, Infections, Nutrition, and Exercise as able. This is dramatically effective, resulting in 91 percent of people with CFS or fibromyalgia improving after more than three months with an average 90 percent increase in quality of life after almost two years.

EL | What kinds of treatment are you working with for long COVID?

JT | There is no lack of effective treatments for long COVID; there is simply lack of physician education. Unfortunately, being a complex illness with low-cost treatments, there is not much financial resource for this to change. But on a brighter note, there is a lot that people can do on their own to both understand their condition and recover.

Simple ways to begin:

1. Start with a high-dose multivitamin with high levels of B complex and at least 150 mg of magnesium. RDA levels are inadequate for this condition.
2. Take a unique form of red ginseng called HRG 80 Red Ginseng Chewable Tablets — one-half to two tablets daily. It does need to be this form as other ginsengs do not have adequate levels of the active components. I recommend the chewables as it significantly cuts the cost. Even one-half tablet a day is enough for many people.
3. I would also add 5 grams of ribose powder twice daily. It looks and tastes like sugar and can be added to any drink or food. I do recommend the bioenergy form used in the study, which can be found in many products. In many people, this combination alone may double their energy.

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