Abstract

   Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a
   disease now well-documented as having arisen commonly from a viral
   infection, but also from other external stressors, like exposure to
   agricultural chemicals, other types of infection, surgery, or other
   severe stress events. Research has shown these events produce a
   systemic molecular inflammatory response and chronic immune activation
   and dysregulation. What has been more difficult to establish is the
   hierarchy of the physiological responses that give rise to the myriad
   of symptoms that ME/CFS patients experience, and why they do not
   resolve and are generally life-long. The severity of the symptoms
   frequently fluctuates through relapse recovery periods, with
   brain-centered symptoms of neuroinflammation, loss of homeostatic
   control, “brain fog” affecting cognitive ability, lack of refreshing
   sleep, and poor response to even small stresses. How these brain
   effects develop with ME/CFS from the initiating external effector,
   whether virus or other cause, is poorly understood and that is what our
   paper aims to address. We propose the hypothesis that following the
   initial stressor event, the subsequent systemic pathology moves to the
   brain via neurovascular pathways or through a dysfunctional blood-brain
   barrier (BBB), resulting in chronic neuroinflammation and leading to a
   sustained illness with chronic relapse recovery cycles. Signaling
   through recognized pathways from the brain back to body physiology is
   likely part of the process by which the illness cycle in the peripheral
   system is sustained and why healing does not occur. By contrast, Long
   COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness
   arising from the single pandemic virus, SARS-CoV-2. We believe the
   ME/CFS-like ongoing effects of Long COVID are arising by very similar
   mechanisms involving neuroinflammation, but likely with some unique
   signaling, resulting from the pathology of the initial SARS-CoV-2
   infection. The fact that there are very similar symptoms in both
   ongoing diseases, despite the diversity in the nature of the initial
   stressors, supports the concept of a similar dysfunctional CNS
   component common to both.

   Keywords: ME/CFS, Long COVID, systemic inflammation, neuroinflammation,
   disease persistence, relapse

Introduction

   Since the 1930s, when documentation of post-viral fatigue illnesses
   first occurred, there have been 75 reported outbreaks of probable viral
   origin that have led to long-term diseases that have the profile of
   Myalgic Encephalomyelitis/Chronic Fatigue syndrome (ME/CFS). Of these,
   the most publicized have been Los Angeles (1934) ([37]1), Akureyri,
   Northern Iceland (1946–1948) ([38]2), the Royal Free Hospital in London
   (1955) ([39]3), Incline Village, Nevada (1984) ([40]4), and in New
   Zealand, Tapanui (1984) ([41]5). That outbreak has become known in New
   Zealand's “health folklore” as “Tapanui flu.” The name ME originated
   from the London outbreak, and the name CFS from that in Incline
   Village, Nevada. These were outbreaks where the initial infectious
   agent affected a relatively modest number of people in the hundreds in
   stark contrast to the current pandemic where nearly 500 million to date
   have been affected. The condition in recent times generally has become
   referred to as ME/CFS, the combined name derived from the European and
   American outbreaks. Connections among these disease outbreaks are
   discussed more comprehensively in Van Elzakker et al. ([42]6). Despite
   their frequency and documented occurrence over a relatively long period
   of time, little research investment into their understanding has
   occurred, perhaps because the outbreaks were isolated geographically,
   involved relatively few people each time and, despite being highly
   debilitating and lifelong, were dwarfed in importance by the more
   common abundant non-communicable diseases. The underlying biology of
   ME/CFS has not been well-understood, with blood screens using standard
   laboratory tests falling within the normal range. Although these
   affected patients were obviously ill, they were given a “clean bill of
   health” often with no medical incentive to dig deeper into the
   condition.

   The worldwide prevalence of ME/CFS has been reported as between 0.4 and
   2.6% among countries and cultures meaning it is ~10-fold more prevalent
   than other fatigue illnesses like multiple sclerosis ([43]7). The lack
   of conclusive biomarkers for a diagnostic laboratory test and the
   ill-defined pathophysiology have hindered an understanding of the
   disease. There have been up to 20 different clinical case definitions
   proposed, and while the Fukuda 1994 diagnostic criterion has been
   commonly used by researchers and clinicians ([44]8), more recent
   criteria like the Canadian Consensus Criteria (2003) developed by an
   international ME panel of experts are now favored ([45]9). These
   criteria focused on core symptoms of post-exertional malaise, fatigue,
   sleep dysfunction, and cognitive dysfunction. Additionally neurological
   and autonomic/neuroendrocrine/immune symptom groups were included
   ([46]9). These were further refined in 2011 to include emphasis on
   inflammation, neuropathology and energy impairments ([47]10). Starting
   in the mid 1980's, the number of studies has accelerated to reveal
   biological dysfunctions in many physiological systems. The known
   features of the pathogenesis of ME/CFS have recently been elegantly
   summarized and compared with what was known in the early stages of the
   post-COVID-19 syndrome ([48]11). They speculated the pathogenesis of
   this illness may be similar to ME/CFS.

   Ironically, not long before the current viral outbreak of SARS-CoV-2,
   wider interest and investment in ME/CFS research began to increase,
   following publication of the US National Academy of Science's Institute
   of Medicine report in 2015 ([49]12) that affirmed ME/CFS was a serious
   disease and had not received proper acknowledgment and recognition from