Are ME/CFS & Long Covid “Post-viral Syndromes”?

And given the current state of ME/CFS & Long Covid research, how can anyone possibly answer that question?

ME/CFS and Long Covid recently got some sympathetic scrutiny as analogous “post-viral conditions” from contributing writer Miriam E. Tucker in an August issue of WebMD Newsletter. Among others, Tucker interviewed Jamie Seltzer, director of scientific and medical outreach at MEAction. Seltzer said her hair “stood on end” when, in early 2020, she heard about a new viral illness sweeping the globe. (1)

Seltzer told Tucker she was concerned that, if the percentage of people with Covid-19 who go on to have long-term symptoms is “similar to what has been seen for other pathogens, then we’re looking at a mass disabling event.”

According to Tucker, neither were ME/CFS researchers surprised by the emergence of Long Covid, “because the same set of symptoms has arisen after many other viruses.”

What causes these symptoms? No one knows, despite the plethora of research into post-viral conditions conducted over the last couple of decades.

Tucker looked into that research, citing a comprehensive 2022 review of “post-acute infection syndromes” (abbreviated PAISs) by an international group helmed by Czech researcher Jan Choutka (U. of Chemistry and Technology, Prague) and Howard Hughes Medical Institute researcher Akiko Iwasaki (Chevy Chase, MD). (2) Their team performed an extensive review of existing literature on PAISs. They examined syndromes that occur after acute infection with 16 viruses; of them, five have “limited or very limited evidence base”; two showed an “association with increased use of ME/CFS diagnosis in health registry”; one each was based on “contradicting or unclear evidence base” and “supporting evidence [that] derives from a single outbreak.” These six of the 16 PAISs examined in their review—37.5%, about one-third—had poor or “unclear” documentation (Table 1 in Choutka et al.).

Noting that they’d excluded some of the most well-known PAISs—like the paralyzing Guillain-Barré syndrome, which readers might recognize—Choutka and colleagues focused on “the unexplained pool [65.5%, about two-thirds] of infection-associated chronic disabilities that appear remarkably consistent in their presentation.”

They describe the ways in which these syndromes resemble one another, including symptoms they share: fatigue and/or exertion intolerance; flu-like and “sickness behavior” like fever, muscle pain, sweating, and irritability; neurological symptoms including brain fog, impaired concentration or memory with no objective diagnostic findings (defective structures visible on an MRI, for example); and chronic or recurring joint pain. Additionally, “studies of objective markers have so far been mostly unrevealing, and the pathogen rarely remains detectable by commonly used methods.” (2)

Choutka and team are reviewing other investigators’ studies, so the question for those primary researchers is: Why are the “commonly used methods” still being used to try to identify the responsible pathogen(s)?

Technology has improved so rapidly over the last two decades—the time period during which most of the studies reviewed were performed—that the numerous and intricate interactions between virus and host are now being unraveled. For more than a decade, it’s been known that some viruses—Epstein-Barr Virus (EBV) and Human Herpes Virus 6 Type A (HHV-6A), in particular—can trigger the production of a “superantigen” named HERV K-18 that “causes deregulation of the immune system,” according to a research team from Tufts University (Boston, MA). (3)

So, there are at least two ways in which viruses can cause disease: (A) acute infection, and (B) acute and/or latent infection that stimulates the production of superantigens.

Recently, a third way that viruses can cause illness has been discovered. In an article published in April 2020, Bhupesh K. Prusty and colleagues at Julius-Maximillians Universitat (Wurzburg, Germany) reported a new, possibly disease-causing, mechanism found in cells with reactivated HHV-6 infection from ME/CFS patients.

Like many viruses, an HHV-6 infection can progress from acute (when the virus is active and can directly cause disease) to latent (when the virus is thought to be inactive) to reactivated (when the virus is once again active and so is potentially able to cause disease).

Prusty et al. discovered that cells with reactivated HHV-6 infections appear to secrete an “activity” that “fractures” (destroys) mitochondria, the cell’s energy producer. This activity also stimulates what they called a coordinated antiviral “program” in uninfected cells. These studies were performed on blood cells from ME/CFS patients. In addition to the program being transferred from cells infected with HHV-6 to cells that were not infected, it can also be transferred from ME/CFS patients’ blood to cells cultured from healthy people. (5)

“Our current data show that only a small fraction of cells needs to be latently infected with HHV-6 to trigger” this program “in neighboring and distant cells lacking HHV-6 DNA,” Prusty and colleagues concluded.

To summarize: First, reactivated HHV-6 infection breaks apart mitochondria, causing the cell to produce less (or no) energy. Second, it causes not only the infected cell but also nearby uninfected cells to secrete molecules that trigger a viral “program.” And third, whatever is causing that viral “program” can be transferred from even a small number of HHV-6A infected cells to healthy cells in the lab.

So, there are at least three ways that viruses can cause disease: (A) acute infection, (B) acute and/or latent infection that stimulates the production of superantigens and, (C) reactivation that triggers a viral “program” that destroys mitochondria and can be spread to healthy cells.

All of which leads us back to the main question: What mechanism causes “post-viral” syndromes? Since researchers don’t seem to be able to find the pathogens responsible, is there some new, still undiscovered mechanism at work?

Meanwhile, finding the answers to those questions becomes ever more urgent.

A recent opinion column in the New York Times by Columbia University professor Zeynep Tufekci examines Long Covid and other post-viral conditions, pointing out that current data are insufficient—at the very least—to describe what’s happening to these patients. “The symptom descriptions for Long Covid are too vague,” she points out. “Do ‘brain fog’ and ‘fatigue’ mean people don’t feel as sharp as they were and are a little off their jogging times, or are they experiencing a cognitive crisis so profound that they cannot find words and are so fatigued that brushing their teeth leaves them unable to get out of bed for the rest of the day?”

And that barely scratches the surface of what Tufekci finds lacking in current studies investigating post-viral syndromes: Some studies have no control groups; some can’t properly separate subgroups of patients because there’s no reliable way to do it; it’s impossible to tell who will benefit from certain treatments because there’s no way to separate subgroups of patients, and more.

Tufekci makes it clear that, worldwide, research into syndromes like Long Covid and ME/CFS is failing.

All of which is concerning, if not surprising, but none of which answers the main question: Are Long Covid, ME/CFS and other illnesses correctly defined as “post-viral” conditions?

As Miami-based ME/CFS researcher Nancy G. Klimas told Tucker in WebMD, “I was taught that there has to be an antigen [such as a viral protein] in the system to drive the immune system to make it create sickness, and the immune system should shut off when it’s done.”

If the syndrome’s assigned pathogen—any of the 16 mentioned by Choutka et al., as well as others that weren’t—is not detectable by the usual methods, what is causing the symptoms? Is a virus hiding in what are called persistent pathogen reservoirs that can stimulate T- and B-cells to cause illness—even years after the acute illness? Could the cause(s) be viral reactivation? Or inability to repair tissue damage from the original infection? Or cytokine stimulation? Molecular mimicry, perhaps? Where do we go from here?

“In addition to basic biomedical research, more needs to be done to refine diagnostic criteria and obtain more reliable estimates of the prevalence and societal burden of these disorders to help shape health-policy decisions,” Choutka and colleagues concluded. “Moreover, we call for unified nomenclature and better conceptualization of post-acute infection symptoms.”

And while we’re at it, could “fatigue” not be described as the primary uniting factor of all the “post-viral syndromes”?

BIBLIOGRAPHY

1. Tucker, Miriam T. “Long COVID Mimics Other Post-Viral Conditions.” WebMD Newsletter, August 24, 2022. https://www.webmd.com/lung/news/20220824/long-covid-mimics-other-post-viral-conditions

2. Choutka, J., Jansari, V., Hornig, M. et al. “Unexplained post-acute infection syndromes.” Nature Medicine 28, 911–923 (2022). https://doi.org/10.1038/s41591-022-01810-6

3. Tai, Albert K.; Luka, Janos; Ablashi, Dharam; Huber, Brigitte T. “HHV-6A infection induces expression of HERV-K18-encoded superantigen.” Journal of Clinical Virology, 2009 Sep; 46(1):47-8. PMID: 19505843 doi: 10.1016/j.jcv.2009.05.019

4. Belén de la Hera, et. al. “Role of the Human Endogenous Retrovirus HERV-K18 in Autoimmune Disease Susceptibility: Study in the Spanish Population and Meta-Analysis.” PLoS One. 2013; 8(4): e62090. doi: 10.1371/journal.pone.0062090

5. Schreiner, P.; Harrer, T.; Scheibenbogen, C.; Lamer, S.; Schlosser, A.; Naviaux, R.K. and Prusty, B.K. “Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.” ImmunoHorizons April 1, 2020; 4: 201-215. doi: https://doi.org/10.4049/immunohorizons.2000006

6. Tufekci, Zeynep. “If You’re Suffering After Being Sick With Covid, It’s Not Just in Your Head.” New York Times, August 25, 2022.