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Long Covid @ Keystone

For people suffering from long COVID's often disabling symptoms, including intense fatigue, breathing troubles, cognitive issues and heart palpitations, the list of scientific unknowns may sound defeating. Most clinical approaches still come down to treating symptoms, rather than identifying and treating underlying causes. And there's still no validated treatment or diagnostic tests.

But researchers, they say, are making progress in the field, and presented their recent findings at one of the first major gatherings dedicated to sharing emerging evidence about the possible root cause of long COVID and implications for treatment, held by the nonprofit Keystone Symposia in Santa Fe, New Mexico last month.

While not by any stretch functional medicine focused, for what it's worth, here are some of the key findings and lines of research presented during the three-day gathering.

(If you'd prefer to jump straight to the functional medicine thinking, have a look at this link, although these recommendations and observations are from 2020. If this topic is of particularly acute interest to you, you might also check in periodically with the IFM's dedicated Covid-19 Functional Medicine Resources page.)

Viral persistence: There's now strong evidence that protein and genetic material from SARS-CoV-2 persist in the blood and tissue of some long COVID patients well after their initial illness. Scientists believe these "viral reservoirs" could be driving many of the problems in long COVID patients, although it isn't yet clear exactly how this is happening — and whether the virus itself is replicating.

And while they are more likely to find viral persistence in the most symptomatic long COVID patients, not everyone with long COVID has it. And more confounding yet, they are also seeing this in some people who feel totally fine — so is this just another red herring?

Activated T-cells: Other leads have come from imaging technology that traces the activity of T cells, a type of white blood cell, which are part of the body's main antiviral immune response.

Dr. Timothy Henrich, of UCSF who first made a name for himself in HIV "cure" research, reported finding activated T cells in the gut wall, lung tissue, certain lymph nodes, the bone marrow, the spinal cord and the brain stem, long after the initial infection.

"You really shouldn't have activated T cells in the spinal cord or the brain stem," he says. "We are seeing evidence of this immune response in areas we don't typically see in the setting of an acute viral infection."

Here too the immunological detective work opens up even more questions: This T cell activity is also present in people who've recovered from an infection and have no long COVID symptoms, although Henrich notes the levels appear to be higher in certain tissues of people with long COVID.

So what does this immune response actually indicate about the underlying cause of the disease?

Henrich notes that this T cell activity could either be A) evidence that the immune system is trying to purge the viral reservoirs, or B) that the immune response has gone awry, possibly in the form of an autoimmune response, and is doing damage, even if the virus has been cleared or is not replicating in those tissues.

Similar questions bedevil researchers pursuing another theory.

Cross-stimulation of otherwise previously quiescent viral infections: Research shows that people with long COVID have high levels of Epstein-Barr antibodies and that an acute COVID infection can trigger reactivation of the virus.

Akiko Iwasaki, a professor of immunobiology at Yale University, says it's well known that this herpesvirus can lead to a "long COVID-like syndrome," but whether or not the reactivation is driving long COVID symptoms — or just an indication of a dysregulated immune system — remains to be seen.

All of those involved in research stress that they don't expect just one answer to long COVID. It's likely that many of these theories about its underlying cause are interrelated. And certain mechanisms may only be causing symptoms in some patients and not others.

Potential role of sex hormones (esp. testosterone): The impetus to look at testosterone was, in part, because of anecdotes from trans individuals suffering from long Covid who reported dramatic improvement while on testosterone therapy.

And why males tended to do worse during an acute bout of COVID-19, long COVID appears to be more prevalent among females.

Professor Iwasaki also shared evidence of reduced cortisol levels in long COVID patients. And, arguably more intriguing, shared separate, unpublished finding that female long COVID patients tend to have reduced testosterone levels. And reduced testosterone levels, in both men and women, correlated with increased T cell activation-- which in turn was associated with greater neurological symptoms and overall higher "symptom burden."

(Curiously, male long Covid patients showed reduced estradiol levels. But it's not clear if these researchers fully appreciate the biochemical interdependence of these two hormones; namely, that estrogen (estradiol) is made from testosterone and that, especially in metabolically unfit older men, testosterone is routinely "aromatized" into estradiol aka estrogen. Time will tell.)

While the researchers made a plea for greater "industry engagement" in this research (and ostensibly the development of potential therapeutics), precious little time or focus was dedicated to looking at the proverbial "big picture." That line of thinking appears still to be relegated to the world of functional medicine-- and will be the subject a follow-up post just as soon as possible.

For now, while also not individualized advice, here is what the IFM faculty have suggested most recently, their focus being on mitochondrial health & function, with nothing (yet) directed at hormones or aberrant immune system activation:

Mitochondrial integrity is essential to maintain an adequate immune response against SARS-CoV-2 infection, and supporting mitochondria may help prevent neuronal complications. IFM’s Mitochondrial Food Plan is an anti-inflammatory, low glycemic, high-quality fat dietary approach that supports healthy mitochondria for improved energy production. The following nutritional supplements (although doses not specified) and lifestyle-based interventions have also been suggested for the treatment of Post-acute Sequelae of Sars-CoV-2 Infection (PASC) symptoms:

  • Antioxidant supplementation: Vitamins C and E, as well as selenium, can counteract excess ROS production.

  • Plant-based diets: Diets high in plant defense compounds with pleiotropic actions that are known to modulate mitochondrial function and induce resolution of inflammation, as well as displaying anti-pathogen function.

  • CoQ10 supplementation: Strategies to target mitochondrial bio-energetics and antioxidant defense include supplemental therapy with CoQ10, an important antioxidant in the mitochondria.

  • N-acetylcysteine (NAC) supplementation: In high doses (≥1,200 mg), NAC acts as an antioxidant through complex mechanisms that can improve situations of oxidative stress. For this reason, it has been proposed to have potential for early administration in patients at greater risk of severe COVID-19.

  • Acetyl-L-carnitine (ALC): ALC is key to mitochondrial function, promoting the expression of nerve growth factors and peripheral nerve regeneration and conduction, and is considered an effective dietary supplement for diabetic neuropathy.

  • Alpha-lipoic acid (ALA): ALA, also known as thioctic acid or simply as lipoic acid, is a powerful antioxidant, acting as a coenzyme in mitochondrial reactions in which glucose is converted into energy.

  • Physical activity: Regular, moderate physical activity enhances immune function and mitochondrial fitness. Moderate intensity training (MIT) is usually performed at around 50-75% of the maximal capacity, often in a continuous fashion (MICT).

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