A neuroinflammatory paradigm can explain Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome and Post-COVID-19 Fatigue Syndrome

Abstract

This thesis illustrates the development of a neuroinflammatory paradigm for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), applicable to Long-COVID related “Post-COVID-19 Fatigue Syndrome” (PCFS).

The brain being devoid of nociceptors, in combination with neuroimaging technology lacking sufficient sensitivity, helps to explain why the chronic but low-level neuroinflammation purported to be present in the brains of ME/CFS (and PCFS) sufferers has gone unreported by patients, and has been largely undetected by scientists, until more recently. Over-activation of microglia and astrocytes is increasingly being proposed to be at the heart of ME/CFS (and PCFS) pathophysiology.

A key Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) study (2014) provided evidence of glial-cell over-activity, implicating neuroinflammation within the brain’s limbic system, of ME/CFS patients. Other cerebral spinal fluid and neuroimaging studies, including a more recent Magnetic Resonance Spectroscopy (MRS)/MRI Thermometry study (2019), have added support to this concept.

Resultant dysfunction of the limbic system and its closely-connected hypothalamus, which in turn leads to a disturbed autonomic nervous system (ANS) and dysfunctional hypothalamic-pituitary-adrenal-axis (HPA-axis) could then account for the diverse range of symptoms reported in ME/CFS (and PCFS). These symptoms include chronic fatigue, flu-like malaise, mood, memory and cognitive problems (limbic system), sleep, taste, visual and thermostatic-control problems (hypothalamus), gastro-intestinal disturbance, cardiovascular problems and hypotension (ANS), as well as increased frequency of urination and lower blood cortisol levels (HPA-axis).

A dysfunctional hypothalamic paraventricular nucleus (PVN), a potentially vulnerable site, within the brains of genetically susceptible people, which functions normally as a stress-control integrator, is proposed to be at the core of ME/CFS (and PCFS) aetiology and pathophysiology.

It is proposed that all triggers of ME/CFS, be they viral (Epstein-Barr Virus is the most common trigger), or non-viral; including other infectious diseases, multiple vaccinations, emotional trauma or chemical toxin shock, share a common triggering mechanism. They are each proposed to manifest themselves as severe physiological stressors, which by a combination of humoral and neural routes, target, the hypothalamic PVN, of genetically susceptible individuals. By exceeding an intrinsic stress-threshold pertaining to the complex neurological circuitry, within the hypothalamic PVN, the triggering stressor is proposed to overload it into a (permanently) iii dysfunctional state.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19), in common with the triggering stressors of ME/CFS, also manifests itself as a severe physiological stressor, due to a cytokine surge at the site of the primary infection (the lungs). This particular stressor is, also, proposed to target the hypothalamic PVN, in genetically susceptible people, thus triggering PCFS. Life’s ongoing physiological stressors, such as physical, mental overexercise, chemical toxin exposure, emotional and financial stress, all of which are known to exacerbate and perpetuate ME/CFS (as well as PCFS) could do so by then targeting a now “compromised” (possibly inflamed) stress-sensitive hypothalamic PVN, by similar routes.

Then if an alternative, but variable (according to fluctuating neuroinflammation of the hypothalamic PVN, itself) stress threshold was exceeded, commonly reported post-exertional malaise (PEM) episodes, more problematic flare-ups, and even more severe prolonged and characteristic relapses could ensue.

It is proposed that a dysfunctional hypothalamic PVN, thereby, acts as an epicentre to a radiating neuroinflammatory response within the brains of ME/CFS (and PCFS) sufferers. A neuroinflammatory pathway, as proposed to be shared by the early-onset stages of several progressive neuroinflammatory (neurodegenerative) diseases could also be shared by ME/CFS, and PCFS. Indeed, this pathway could be shared by other potentially nonprogressive neuroinflammatory disorders, such as the closely-related fibromyalgia, mental health disorders, epilepsy, and migraines.

Might then the “drivers” of the inflammatory process, which sustain glial-cell activation (and neuroinflammation), in ME/CFS (and PCFS), be the perpetuating stressors, themselves, acting in combination with a now “compromised” and stress-sensitive hypothalamic PVN? If so, what then might be the mechanistic detail linking a stressor-targeted hypothalamic PVN and microglial activation in ME/CFS (and PCFS)?

One attractive scenario requiring further investigation involves the release of corticotrophin releasing hormone (CRH), which is released naturally by the hypothalamic PVN due to stress. The chronic release of CRH from a stress-sensitive, dysfunctional hypothalamic PVN might induce microglia activation, leading to chronic neuroinflammation, via the stimulation of mast-cells.

Two papers were published in relation to this neuroinflammatory paradigm for ME/CFS (2018, 2019), followed by another paper (2021), in which a paradigm was presented to explain the more recently emergent, but equally perplexing, Long-COVID related “PostCOVID-19 Fatigue Syndrome” (PCFS).

The neuroinflammatory model presented is both iv coherent and unifying for all triggering stressors and perpetuating stressors of ME/CFS (& PCFS), without the need for subtypes (as many other models require), but it does require validation. To this effect, it is hoped that this neuroinflammatory model will be both thought-provoking, as well as providing a framework for scientific researchers to test, critique, modify, and develop, into the future.

More brain-focussed research, using increasingly sophisticated neuroimaging technology (especially enhanced PET/MRI) is recommended. Then, a brain-signature for both ME/CFS (and PCFS) might even become attainable, within the next decade, perhaps.

Long-COVID related PCFS, affecting millions of people worldwide, presents a golden opportunity for in-depth longitudinal neuroimaging studies (following patients through relapse-recovery cycles) to develop a better understanding of PCFS (and ME/CFS) pathophysiology.

Source: Mackay, A. A neuroinflammatory paradigm can explain Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome and Post-COVID-19 Fatigue Syndrome. PhD Thesis. University of Otago, New Zealand.  https://ourarchive.otago.ac.nz/bitstream/handle/10523/15089/MackayAngus2021PhD.pdf?sequence=1&isAllowed=y (PDF file)

Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Background and Objectives: Post-exertional malaise (PEM) is the hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but there has been little effort to quantitate the duration of PEM symptoms following a known exertional stressor.

Using a Symptom Severity Scale (SSS) that includes nine common symptoms of ME/CFS, we sought to characterize the duration and severity of PEM symptoms following two cardiopulmonary exercise tests separated by 24 h (2-day CPET).

Materials and Methods: Eighty persons with ME/CFS and 64 controls (CTL) underwent a 2-day CPET. ME/CFS subjects met the Canadian Clinical Criteria for diagnosis of ME/CFS; controls were healthy but not participating in regular physical activity. All subjects who met maximal effort criteria on both CPETs were included.

SSS scores were obtained at baseline, immediately prior to both CPETs, the day after the second CPET, and every two days after the CPET-1 for 10 days.

Results: There was a highly significant difference in judged recovery time (ME/CFS = 12.7 ± 1.2 d; CTL = 2.1 ± 0.2 d, mean ± s.e.m., Chi2 = 90.1, p < 0.0001).

The range of ME/CFS patient recovery was 1–64 days, while the range in CTL was 1–10 days; one subject with ME/CFS had not recovered after one year and was not included in the analysis.

Less than 10% of subjects with ME/CFS took more than three weeks to recover. There was no difference in recovery time based on the level of pre-test symptoms prior to CPET-1 (F = 1.12, p = 0.33).

Mean SSS scores at baseline were significantly higher than at pre-CPET-1 (5.70 ± 0.16 vs. 4.02 ± 0.18, p < 0.0001). Pharmacokinetic models showed an extremely prolonged decay of the PEM response (Chi2 > 22, p < 0.0001) to the 2-day CPET.

Conclusions: ME/CFS subjects took an average of about two weeks to recover from a 2-day CPET, whereas sedentary controls needed only two days. These data quantitate the prolonged recovery time in ME/CFS and improve the ability to obtain well-informed consent prior to doing exercise testing in persons with ME/CFS. Quantitative monitoring of PEM symptoms may provide a method to help manage PEM.

Source: Moore GE, Keller BA, Stevens J, Mao X, Stevens SR, Chia JK, Levine SM, Franconi CJ, Hanson MR. Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Medicina. 2023; 59(3):571. https://doi.org/10.3390/medicina59030571 (Full text)

Objective sleep measures in chronic fatigue syndrome patients: A systematic review and meta-analysis

Abstract:

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report disrupted and unrefreshing sleep in association with worsened fatigue symptoms. However, the nature and magnitude of sleep architecture alteration in ME/CFS is not known, with studies using objective sleep measures in ME/CFS generating contradictory results.

The current manuscript aimed to review and meta-analyse of case-control studies with objective sleep measures in ME/CSF. A search was conducted in PubMed, Scopus, Medline, Google Scholar, and Psychoinfo databases.

After review, 24 studies were included in the meta-analysis, including 20 studies with 801 adults (ME/CFS = 426; controls = 375), and 4 studies with 477 adolescents (ME/CFS = 242; controls = 235), who underwent objective measurement of sleep.

Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, decreased sleep efficiency, decreased stage 2 sleep, increased Stage 3, and longer rapid eye movement sleep latency.

However, adolescent ME/CFS patients had longer time in bed, longer total sleep time, longer sleep onset latency, and reduced sleep efficiency.

The meta-analysis results demonstrate that sleep is altered in ME/CFS, with changes seeming to differ between adolescent and adults, and suggesting sympathetic and parasympathetic nervous system alterations in ME/CFS.

Source: Abdalla Z. Mohamed, Thu Andersen, Sanja Radovic, Peter Del Fante, Richard Kwiatek, Vince Calhoun, Sandeep Bhuta, Daniel F. Hermens, Jim Lagopoulos, Zack Shan. Objective sleep measures in chronic fatigue syndrome patients: A systematic review and meta-analysis. Sleep Medicine Reviews, 2023, 101771.  https://www.sciencedirect.com/science/article/abs/pii/S1087079223000278

Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood.

While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person.

A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options.

Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination.

Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation.

The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients.

Source: Tate WP, Walker MOM, Peppercorn K, Blair ALH, Edgar CD. Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID. International Journal of Molecular Sciences. 2023; 24(6):5124. https://doi.org/10.3390/ijms24065124 (Full text)

Myalgic Encephalitis/Chronic Fatigue Syndrome: Diagnostic and Therapeutic Approach and Biological Research

Abstract:

Myalgic encephalitis/chronic fatigue syndrome, an intractable disease characterized by profound fatigue, sleep disturbance, cognitive impairment, and orthostatic intolerance, among other features, often occurs after infectious episodes. Patients experience various types of chronic pain; however, post-exertional malaise is the most significant feature, which requires pacing. In this article, I summarize the current diagnostic and therapeutic approaches and describe recent biological research in this domain.

Source: Sato W. [Myalgic Encephalitis/Chronic Fatigue Syndrome: Diagnostic and Therapeutic Approach and Biological Research]. Brain Nerve. 2023 Mar;75(3):217-225. Japanese. doi: 10.11477/mf.1416202311. PMID: 36890757. https://pubmed.ncbi.nlm.nih.gov/36890757/ [Article in Japanese]

Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID

Abstract:

Background: COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID).

Methods: We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalization and up to 9 months of convalescence following COVID-19, respiratory syncytial virus (RSV) or influenza A (flu). Progressive fibrosing interstitial lung disease (PFILD) patients were included a positive control for severe, ongoing lung injury.

Results: Monocyte alterations in acute COVID-19 patients included aberrant expression of leucocyte migration molecules, continuing into convalescence (n=142) and corresponding to specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of chemokine receptor CXCR6 (p<0.0001) and adhesion molecule PSGL-1 (p<0.01), alongside preferential migration of monocytes towards CXCR6 ligand CXCL16 (p<0.05) which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in PFILD patients (p<0.001) confirming a role for the CXCR6-CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited sustained reduction of the prostaglandin-generating enzyme COX-2 (p<0.01) and CXCR2 expression (p<0.05). These monocyte changes were not present in RSV or flu convalescence.

Conclusions: Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.

Source: Scott NA, Pearmain L, Knight SB, Brand O, Morgan DJ, Jagger C, Harbach S, Khan S, Shuwa HA, Franklin M, Kästele V, Williams T, Prise I, McClure FA, Hackney P, Smith L, Menon M, Konkel JE, Lawless C, Wilson J, Mathioudakis AG, Stanel SC, Ustianowski A, Lindergard G, Brij S, Diar Bakerly N, Dark P, Brightling C, Rivera-Ortega P, Lord GM, Horsley A; CIRCO; Piper Hanley K, Felton T, Simpson A, Grainger JR, Hussell T, Mann ER. Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID. Eur Respir J. 2023 Mar 15:2202226. doi: 10.1183/13993003.02226-2022. Epub ahead of print. PMID: 36922030. https://erj.ersjournals.com/content/early/2023/02/23/13993003.02226-2022 (Full article available as PDF file)

Demographic And Clinical Factors Associated With Long COVID

Abstract:

Risk factors for postacute sequelae of SARS-CoV-2 infection (“long COVID”) in community-dwelling populations remain poorly understood. Large-scale data, follow-up, comparison groups, and a consensus definition of long COVID are often lacking. Using data from the OptumLabs Data Warehouse on a nationwide sample of commercial and Medicare Advantage enrollees from the period January 2019 through March 2022, we examined demographic and clinical factors associated with long COVID, using two definitions of people who suffer symptoms long after they were first diagnosed with COVID-19 (“long haulers”).

We identified 8,329 long haulers using the narrow definition (diagnosis code), 207,537 long haulers using the broad definition (symptom based), and 600,161 non–long haulers (comparison group).

On average, long haulers were older and more likely female, with more comorbidities. Among narrow-definition long haulers, the leading risk factors for long COVID included hypertension, chronic lung disease, obesity, diabetes, and depression. Their time between initial COVID-19 diagnosis and diagnosis of long COVID averaged 250 days, with racial and ethnic differences. Broad-definition long haulers exhibited similar risk factors. Distinguishing long COVID from the progression of underlying conditions can be challenging, but further study may advance the evidence base related to the identification, causes, and consequences of long COVID.

Source: Song Z, Giuriato M. Demographic And Clinical Factors Associated With Long COVID. Health Aff (Millwood). 2023 Mar;42(3):433-442. doi: 10.1377/hlthaff.2022.00991. PMID: 36877912. https://pubmed.ncbi.nlm.nih.gov/36877912/

A 2-day cardiopulmonary exercise test in chronic fatigue syndrome patients who were exposed to humidifier disinfectants

Abstract:

Some survivors of humidifier disinfectants (HDs) complain of chronic, inexplicable fatigue, and post-exertional malaise (PEM). Two-day cardiopulmonary exercise tests (CPETs) performed 24 hours apart (2-day CPET protocol) are increasingly employed to evaluate PEM and related disabilities among individuals with chronic fatigue syndrome (CFS). The purpose of this study was to assess the reproducibility of CPET variables in individuals who had been exposed to HD and to show that 2-day CPET is an objective means of differentiating between fatigue conditions in people with CFS symptoms who have been exposed to HDs.

Twenty-nine HD survivors with CFS symptoms were enrolled in this study. To document and assess PEM in CFS, a 2-day CPET was conducted to measure baseline functional capacity (CPET1) and provoke PEM. Twenty-four hours later, a second CPET assessed changes in related variables, focusing on PEM effects on functional capacity. This CPET also measured changes in energy production and physiological function, objectively documenting PEM effects.

In the 2-day CPET, the peak oxygen consumption (VO2peak), VO2 at ventilatory threshold (VO2@VT), time to reach VO2peak, and time to reach VO2@VT were significantly decreased (p<0.001). The peak O2 pulse and O2 pulse at VT also decreased significantly (p<0.001). A 6-minute walk test revealed significantly decreased distance (p<0.01). This is the first study to conduct a 2-day consecutive CPET in previously exposed HD participants with CFS symptoms.

Our results confirm previous work that demonstrated abnormal responses to PEM in CFS patients. Therefore, a 2-day CPET is an objective measure to differentiate fatigue conditions in people with CFS symptoms who have been exposed to HDs.

Source: Leem JH, Jeon HE, Nam H, Kim HC, Joa KL. A 2-day cardiopulmonary exercise test in chronic fatigue syndrome patients who were exposed to humidifier disinfectants. Environ Anal Health Toxicol. 2022 Dec;37(4):e2022033-0. doi: 10.5620/eaht.2022033. Epub 2022 Nov 3. PMID: 36916046; PMCID: PMC10014750. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10014750/ (Full text)

Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Background: Long COVID describes a condition with symptoms that linger for months to years following acute COVID-19. Many of these Long COVID symptoms are like those experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Objective: We wanted to determine if people with Long COVID experienced post-exertional malaise (PEM), the hallmark symptom of ME/CFS, and if so, how it compared to PEM experienced by patients with ME/CFS.

Methods: A questionnaire that asked about the domains of PEM including triggers, experience, recovery, and prevention was administered to 80 people seeking care for Long COVID at Bateman Horne Center. Their responses were compared to responses about PEM given by 151 patients with ME/CFS using chi-square tests of independence.

Results: All but one Long COVID respondent reported having PEM. There were many significant differences in the types of PEM triggers, symptoms experienced during PEM, and ways to recover and prevent PEM between Long COVID and ME/CFS. Similarities between Long COVID and ME/CFS included low and medium physical and cognitive exertion to trigger PEM, symptoms of fatigue, pain, immune reaction, neurologic, orthostatic intolerance, and gastrointestinal symptoms during PEM, rest to recover from PEM, and pacing to prevent PEM.

Conclusion: People with Long COVID experience PEM. There were significant differences in PEM experienced by people with Long COVID compared to patients with ME/CFS. This may be due to the newness of Long COVID, not knowing what exertional intolerance is or how to manage it.

Source: Vernon SD, Hartle M, Sullivan K, Bell J, Abbaszadeh S, Unutmaz D, Bateman L. Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Work. 2023 Mar 7. doi: 10.3233/WOR-220581. Epub ahead of print. PMID: 36911963. https://content.iospress.com/articles/work/wor220581 (Full text)

Predictors of impaired functioning among long COVID patients

Abstract:

Background: There is limited information on what acute factors predict more long-term symptoms from COVID-19.

Objective: Our objective was to conduct an exploratory factor analysis of self-reported symptoms at two time points of Long COVID-19.

Methods: Data from patients with Long COVID-19 were collected at the initial two weeks of contracting SARS CoV-2 and the most recent two weeks, with a mean duration of 21.7 weeks between the two-time points. At time point 2, participants also complete the Coronavirus Impact Scale (CIS), measuring how the COVID-19 pandemic affected various dimensions of their lives (e.g., routine, access to medical care, social/family support, etc.).

Results: At time 1, a three-factor model emerged consisting of Cognitive Dysfunction, Autonomic Dysfunction and Gastrointestinal Dysfunction. The analysis of time 2 resulted in a three-factor model consisting of cognitive dysfunction, autonomic dysfunction, and post-exertional malaise. Using factor scores from time 1, the Autonomic Dysfunction and the Gastrointestinal Dysfunction factor scores significantly predicted the CIS summary score at time two. In addition, the same two factor scores at time 1 predicted the occurrence of myalgic encephalomyelitis/chronic fatigue syndrome at time 2.

Conclusion: As Cognitive and Autonomic Dysfunction emerged as factors for both time points, suggesting health care workers might want to pay particular attention to these factors that might be related to later symptoms and difficulties with returning to pre-illness family life and work functioning.

Source: Jason LA, Dorri JA. Predictors of impaired functioning among long COVID patients. Work. 2023 Mar 8. doi: 10.3233/WOR-220428. Epub ahead of print. PMID: 36911958. https://content.iospress.com/articles/work/wor220428 (Full text)