Research

Replicated blood-based biomarkers for Myalgic Encephalomyelitis not explicable by inactivity

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Myalgic Encephalomyelitis (ME; sometimes referred to as chronic fatigue syndrome) is a relatively common and female-biased disease of unknown pathogenesis that profoundly decreases patients' health-related quality-of-life. ME diagnosis is hindered by the absence of robustly-defined and specific biomarkers that are easily measured from available sources such as blood, and unaffected by ME patients' low level of physical activity. Previous studies of blood biomarkers have not yielded replicated results, perhaps due to low study sample sizes (n<100). Here, we use UK Biobank (UKB) data for up to 1,455 ME cases and 131,303 population controls to discover hundreds of molecular and cellular blood traits that differ significantly between cases and controls. Importantly, 116 of these traits are replicated, as they are significant for both female and male cohorts. Our analysis used semi-parametric efficient estimators, an initial Super Learner fit followed by a one-step correction, three types of mediators, and natural direct and indirect estimands, to decompose the average effect of ME status on molecular and cellular traits. Strikingly, these trait differences cannot be explained by ME cases' restricted activity. Of 3,237 traits considered, ME status had a significant effect on only one, via the "Duration of walk" (UKB field 874) mediator. By contrast, ME status had a significant direct effect on 290 traits (9%). As expected, these effects became more significant with increased stringency of case and control definition. Significant female and male traits were indicative of chronic inflammation, insulin resistance and liver disease. Individually, significant effects on blood traits, however, were not sufficient to cleanly distinguish cases from controls. Nevertheless, their large number, lack of sex-bias, and strong significance, despite the 'healthy volunteer' selection bias of UKB participants, keep alive the future ambition of a blood-based biomarker panel for accurate ME diagnosis.

Why the Psychosomatic View on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Inconsistent with Current Evidence and Harmful to Patients

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"Since 1969, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been classified as a neurological disease in the International Classification of Diseases by the World Health Organization. Although numerous studies over time have uncovered organic abnormalities in patients with ME/CFS, and the majority of researchers to date classify the disease as organic, many physicians still believe that ME/CFS is a psychosomatic illness. In this article, we show how detrimental this belief is to the care and well-being of affected patients and, as a consequence, how important the education of physicians and the public is to stop misdiagnosis, mistreatment, and stigmatization on the grounds of incorrect psychosomatic attributions about the etiology and clinical course of ME/CFS."

Study Finds Fatigued ME/CFS Brains Unable to Adapt to Cognitive Stress

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"BOLD MRIs sound like the ticket for diseases like chronic fatigue syndrome (ME/CFS) and long COVID. BOLD MRIs measure blood oxygen levels (energy production) across the brain and what could be more telling than that? 

Our brains are never always turned on – that would take too much energy. Instead, when a part of the brain is needed – say, during cognitive activity – the mitochondria in that part of the brain take up more oxygen in the blood. Quickly and efficiently transporting blood to the active region not only determines how well tasks are carried out but also plays an important role in the “energy economics” of the brain. Sluggish blood flows result in the brain working overhard to carry out tasks.

 

BOLD MRIs use blood oxygen levels to determine which parts of the brain are active. By having people with ME/CFS and healthy controls engage in a task, and comparing which parts of the brain get activated, researchers can determine if the different parts of the brain are getting activated (or not activated) in chronic fatigue syndrome (ME/CFS).

Past brain imaging studies indicate that people with ME/CFS have to recruit more regions of the brain than normal to complete cognitive tasks. This suggests their brains are less efficient and require more energy to get cognitive tasks done.

The slowed processing speed cognitive tests have found in ME/CFS appears to make sense in this context; inefficient ME/CFS brains would naturally slow information processing speed down, making it more difficult to follow discussions, retain information while reading, etc. Interestingly, IQ levels don’t appear to be changed – it’s the ability to process information."

Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - PMC (nih.gov)

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"The underlying molecular basis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”), and variably presenting multi-system symptoms, ME/CFS is a complex disease, which demands a concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is mostly comprised of disturbances to immunological and inflammatory pathways, autonomic and neurological dysfunction, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiota disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift. Due to the variability of non-overlapping symptom presentation or precipitating events, such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments."

Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians (degruyter.com)

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"This review was written from the viewpoint of the treating clinician to educate health care professionals and the public about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). It includes: the clinical definition of ME/CFS with emphasis on how to diagnose ME/CFS; the etiology, pathophysiology, management approach, long-term prognosis and economic cost of ME/CFS. After reading this review, you will be better able to diagnose and treat your patients with ME/CFS using the tools and information provided. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic medical condition characterized by symptom clusters that include: pathological fatigue and malaise that is worse after exertion, cognitive dysfunction, immune dysfunction, unrefreshing sleep, pain, autonomic dysfunction, neuroendocrine and immune symptoms. ME/CFS is common, often severely disabling and costly. The Institute of Medicine (IOM) reviewed the ME/CFS literature and estimates that between 836,000 and 2.5 million Americans have ME/CFS at a cost of between 17 and 24 billion dollars annually in the US. The IOM suggested a new name for ME/CFS and called it Systemic Exertion Intolerance Disease (SEID). SEID’s diagnostic criteria are less specific and do not exclude psychiatric disorders in the criteria. The 2010 Canadian Community Health Survey discovered that 29% of patients with ME/CFS had unmet health care needs and 20% had food insecurity – lack of access to sufficient healthy foods. ME/CFS can be severely disabling and cause patients to be bedridden. Yet most patients (80%) struggle to get a diagnosis because doctors have not been taught how to diagnose or treat ME/CFS in medical schools or in their post-graduate educational training. Consequently, the patients with ME/CFS suffer. They are not diagnosed with ME/CFS and are not treated accordingly. Instead of compassionate care from their doctors, they are often ridiculed by the very people from whom they seek help. The precise etiology of ME/CFS remains unknown, but recent advances and research discoveries are beginning to shed light on the enigma of this disease including the following contributors: infectious, genetic, immune, cognitive including sleep, metabolic and biochemical abnormalities. Management of patients with ME/CFS is supportive symptomatic treatment with a patient centered care approach that begins with the symptoms that are most troublesome for the patient. Pacing of activities with strategic rest periods is, in our opinion, the most important coping strategy patients can learn to better manage their illness and stop their post-exertional fatigue and malaise. Pacing allows patients to regain the ability to plan activities and begin to make slow incremental improvements in functionality."

"Collection of peer reviewed case reports and studies citing adverse effects post COVID vaccination.

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Postural Orthostatic Tachycardia Syndrome (POTS): A critical assessment - PMC (nih.gov)

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Although diagnostic criteria have been developed characterizing postural orthostatic tachycardia syndrome (POTS), no single set of criteria is universally accepted. Furthermore, there are gaps in the present criteria used to identify individuals who have this condition. The reproducibility of the physiological findings, the relationship of symptoms to physiological findings, the presence of symptoms alone without any physiological findings and the response to various interventions confuse rather than clarify this condition. As many disease entities can be confused with POTS, it becomes critical to identify what this syndrome is. What appears to be POTS may be an underlying condition that requires specific therapy. POTS is not simply orthostatic intolerance and symptoms or intermittent orthostatic tachycardia but the syndrome needs to be characterized over time and with reproducibility. Here we address critical issues regarding the pathophysiology and diagnosis of POTS in an attempt to arrive at a rational approach to categorize the syndrome with the hope that it may help both better identify individuals and better understand approaches to therapy.

Small fiber neuropathy associated with SARS-CoV-2 infection - PubMed (nih.gov)

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"Introduction/aims: The development and persistence of neurological symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is referred to as "long-haul" syndrome. We aimed to determine whether small fiber neuropathy (SFN) was associated with SARS-CoV-2 infection.

Methods: We retrospectively studied the clinical features and outcomes of patients who were referred to us between May 2020 and May 2021 for painful paresthesia and numbness that developed during or after SARS-CoV-2 infection and who had nerve conduction studies showing no evidence of a large fiber polyneuropathy.

Results: We identified 13 patients, Eight women and five men with age ranging from 38-67 y. Follow-up duration ranged from 8 to 12 mo. All patients developed new-onset paresthesias within 2 mo following SARS-CoV-2 infection, with an acute onset in seven and co-existing autonomic symptoms in seven. Three patients had pre-existing but controlled neuropathy risk factors. Skin biopsy confirmed SFN in six, all of whom showed both neuropathy symptoms and signs, and two also showed autonomic dysfunction by autonomic function testing (AFT). Of the remaining seven patients who had normal skin biopsies, six showed no clinical neuropathy signs and one exhibited signs and had abnormal AFT. Two patients with markedly reduced intraepidermal nerve fiber densities and one with normal skin biopsy had severe and moderate coronavirus disease 2019 (COVID-19); the remainder experienced mild COVID-19 symptoms. Nine patients received symptomatic neuropathy treatment with paresthesias controlled in seven (77.8%).

Discussion: Our findings suggest that symptoms of SFN may develop during or shortly after COVID-19. SFN may underlie the paresthesias associated with long-haul post-COVID-19 symptoms."

Hyper-inflammation caused by COVID-19 may be mediated by mast cell activation (MCA) which has also been hypothesized to cause Long-COVID (LC) symptoms.

 

We determined prevalence/severity of MCA symptoms in LC.

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Methods

Adults in LC-focused Facebook support groups were recruited for online assessment of symptoms before and after COVID-19. Questions included presence and severity of known MCA and LC symptoms and validated assessments of fatigue and quality of life. General population controls and mast cell activation syndrome (MCAS) patients were recruited for comparison if they were ≥18 years of age and never had overt COVID-19 symptoms.

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Results

There were 136 LC subjects (89.7% females, age 46.9 ±12.9 years), 136 controls (65.4% females, age 49.2 ±15.5), and 80 MCAS patients (85.0% females, age 47.7 ±16.4). Pre-COVID-19 LC subjects and controls had virtually identical MCA symptom and severity analysis. Post-COVID-19 LC subjects and MCAS patients prior to treatment had virtually identical MCA symptom and severity analysis.

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Conclusions

MCA symptoms were increased in LC and mimicked the symptoms and severity reported by patients who have MCAS. Increased activation of aberrant mast cells induced by SARS-CoV-2 infection by various mechanisms may underlie part of the pathophysiology of LC, possibly suggesting routes to effective therapy.