ME/CFS and Post-COVID Syndrome: A Common Neuroimmune Ground? 2022 Ryabkova et al

Sly Saint

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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground?

Abstract
:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown etiology, sharing a similar clinical presentation with the increasingly recognized post-COVID syndrome.

We performed the first cross-sectional study of ME/CFS in a community population in Russia.
Then we described and compared some clinical and pathophysiological characteristics of ME/CFS and post-COVID syndrome as neuroimmune disorders.

Of the cohort of 76 individuals who suggested themselves as suffering from ME/CFS, 56 were diagnosed with ME/CFS by clinicians according to ≥1 of the four most commonly used case definitions.

Of the cohort of 14 individuals with post-COVID-19 syndrome, 14 met the diagnostic criteria for ME/CFS. The severity of anxiety/depressive symptoms did not correlate with the severity of fatigue either in ME/CFS or in post-COVID ME/CFS.

Still, a positive correlation was found between the severity of fatigue and 20 other symptoms of ME/CFS related to the domains of “post-exertional exhaustion”, “immune dysfunction”, “sleep disturbances”, “dysfunction of the autonomic nervous system”, “neurological sensory/motor disorders” and “pain syndromes”.

Immunological abnormalities were identified in 12/12 patients with ME/CFS according to the results of laboratory testing. The prevalence of postural orthostatic tachycardia assessed in the active orthostatic test amounted to 37.5% in ME/CFS and 75.0% in post-COVID ME/CFS (the latter was higher than in healthy controls, p = 0.02). There was a more pronounced increase in heart rate starting from the 6th minute of the test in post-COVID ME/CFS compared with the control group.

Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls. The identified laser doppler flowmetry pattern corresponded to the hyperemic form of microcirculation disorders usually observed in acute inflammatory response or in case of systemic vasoconstriction failure.

https://www.mdpi.com/2075-4418/13/1/66

Peer-Review Record
https://www.mdpi.com/2075-4418/13/1/66/review_report
 
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Yes, and from the abstract, a well-informed team.
Varvara A. Ryabkova 1,2,*
Natalia Y. Gavrilova 1,
Tamara V. Fedotkina 1,3,
Leonid P. Churilov 1,4,
Yehuda Shoenfeld 1,5,6

1 Laboratory of the Mosaic of Autoimmunity and Department of Pathology, Saint Petersburg State University, 199034 Saint-Petersburg, Russia
2 Department of Hospital Therapy Named after Academician M.V. Chernorutskii, Research Institute of Rheumatology and Allergology, Pavlov First Saint Petersburg State Medical University,197022 Saint-Petersburg, Russia
3 National Medical Research Center Named after V. A. Almazov, 197341 Saint Petersburg, Russia
4 Saint Petersburg Research Institute of Phthisiopulmonology, 191036 Saint Petersburg, Russia
5 Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Ramat-Gan 52621, Israel
6 Ariel University, Ariel 98603, Israel

This is interesting
Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls. The identified laser doppler flowmetry pattern corresponded to the hyperemic form of microcirculation disorders usually observed in acute inflammatory response or in case of systemic vasoconstriction failure.
 
To date, the cases of ME/CFS in Russia have neither been reported in the English-language medical literature nor have their prevalence estimated. There are currently no ME/CFS clinical services in Russia. Given the global prevalence of ME/CFS, it could be suggested that more than 2.5 million Russian citizens may suffer from ME/CFS remaining undiagnosed.


Previous studies have shown a high propensity of patients with ME/CFS to be misdiagnosed with a psychiatric condition [11]. At the same time, adults with ME/CFS frequently experience co-morbid depression and/or anxiety. Whether these mental health comorbidities relate to the severity of fatigue remains unknown.

We hypothesized that ME/CFS and post-COVID syndrome are not primary men- tal health conditions but share some clinical features and common pathophysiological mechanisms related to autonomic dysfunction and microcirculation disorder.

Three cohorts were formed:

A cohort of patients from 18 to 75 years old who met ≥1 of the 4 most commonly used ME/CFS case definitions (the Fukuda et al. (1994) CFS criteria [13], the Canadian ME/CFS criteria [14], the Myalgic Encephalomyelitis International Consensus Criteria (ME-ICC) [15], and the Institute of Medicine criteria), in whom the onset of the disease was not associated with COVID-19;

A cohort of patients from 18 to 75 years old who met ≥1 of the 4 most commonly used ME/CFS case definitions and those symptoms developed following COVID-19;

Control group (healthy volunteers from 18 to 75 years old).
 
Orthostatic testing
We performed the test no later than 4 p.m. as orthostatic intolerance is more pronounced in the morning.
Interesting and matches my experience - I wonder how many OI studies have controlled for that.

Test was a supine to standing test, 10 minutes of standing

In total, 6/16 people in cohort 1[ME/CFS], 6/8 people in cohort 2 [ME/CFS after Covid], and 1/6 healthy controls met the criteria for postural orthostatic tachycardia syndrome (POTS). As can be seen from Table 7, POTS was statistically significantly more frequent in the ME/CFS group that developed after COVID-19 than in the control group of healthy individuals.

An alternative form of orthostatic intolerance, i.e., orthostatic hypotension, was de- tected only in one person in cohort 1, one person in cohort 3, and none of the people in cohort 2.

To test the hypothesis that the hemodynamic disorder of the POTS type is one of the characteristics of the ME/CFS that developed after COVID-19 and that there exists a causal association between these two conditions rather than a coincidence, we calculated the average increase in heart rate relative to the basal values in all three study cohorts for each minute of the test. Pairwise comparison of these values between cohorts at each minute of the test revealed that the ME/CFS developing after COVID-19 was characterized by a statistically more pronounced increase in heart rate at the 6th, 7th, 8th, 9th, and 10th minute of the test compared with the control group and at the 8th and 9th minutes of the test compared with the ME/CFS developed outside the context of COVID-19. These results support our hypothesis.
Smart analysis - they found it was the sustained increase in heart rate that differentiated the OI in the disease participants from the controls

edit to add:
It is important to note that in 4/13 people who met POTS criteria in our study, the required increase in heart rate was achieved only at the 8–10th minute of the active orthostatic test. This confirms the practice of carrying out the test in its complete (within 10 min) and not abridged (5 min) version.


Immune cells
Nothing much there I think, in very small samples, apart from this
The serum levels of interferons (IFNs) and basal and induced levels of the IFNs secretion by leukocytes were analyzed in four people. All of them had an increase in serum IFNα levels. Moreover, the induced production of IFNα by leukocytes was reduced in 3/4 of the people. The induced secretion of IL-1b, measured in three people, was markedly increased in all patients.
 
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Microcirculation
A non-invasive study of blood microcirculation parameters using the LDF method was carried out on 10 participants from cohort 1, 7 participants from cohort 2, and 7 healthy individuals.
Laser doppler flowmetry

Screen Shot 2024-06-21 at 8.22.37 am.png
Flow of blood is influenced by
1. passive mechanisms (in terms of the blood vessel): the pulse from the heart and the respiratory pump (I assume movement of the body due to breathing), and
2. active mechanisms - oscillations of the vessel due to sympathetic nerve fibres, smooth muscle in the vascular wall and molecules from the endothelium

M—average value of tissue perfusion with blood,
σ—mean square deviation of M oscillations in a given time interval,
vALF—contribution of low-frequency oscillations (0.05–0.2 Hz) to the total power of the spectrum of biorhythms;
vAHF— contribution of high-frequency oscillations (0.2–0.4 Hz) to the total power of the spectrum of biorhythms;
vACF—contribution of pulse frequency oscillations (0.8–1.6 Hz) to the total power of the biorhythms;
IFM—the oscillation index;
R—vascular resistance;
CT—microvascular tone,
r—effect size.

Screen Shot 2024-06-21 at 8.34.07 am.png

(There seems to be an error with the headings for the p values - I think the last column should be 1st versus 2nd ie ME/CFS versus post-covid ME/CFS)

there was a statistically significant increase in the average value of tissue perfusion with blood and a decrease in IFM in participants with ME/CFS, including ME/CFS developed following COVID-19, compared with the control group. There was a statistically significant decrease in the contribution of low-frequency oscilla- tions (0.05–0.2 Hz) to the total power of the spectrum of biorhythms detected in the cohort of ME/CFS that developed after COVID-19. In the case of ME/CFS of a different origin, this decrease was at the border of statistical significance. At the same time, statistically significant differences between cohorts 1 and 2 were revealed only in terms of vascular resistance, which was higher in the first cohort.


The rhythmic characteristics of oscillatory processes in the microcirculation system are useful for the diagnosis of many diseases related to the changes in the microcirculation [36]. The LDF method allows a non-invasive assessment of human blood microcirculation sys- tem disturbances. In this work, LDF was applied to assess the dynamic characteristics of microcirculation in ME/CFS, including post-COVID genesis (in the latter subgroup—it was done for the first time, to the best of our knowledge). A change in the microcirculation index (increase or decrease) characterizes, respectively, an increase or decrease in perfusion. Its increase can be associated with a lower tonus of the arterioles, which leads to an arterial hyperemia, or with the congestion of blood in the venules and venous hyperemia. Regard- ing the regulation of microcirculation, there are “active” and “passive” mechanisms. The “passive” mechanisms include external factors that act outside the microcirculatory bed: a pulse wave and the suction action of the “respiratory pump” from the veins. “Active” factors directly affect the vessels of the microvasculature by periodically changing the resistance of blood vessels to blood flow through vasomotions and creating transverse fluctuations in blood flow. These active factors are sympathetic nerve fibers, smooth muscle cells of the vascular wall, and endothelium-derived regulatory molecules. When carrying out spectral analysis, the active factors correspond to low-frequency oscillations [37]. There are several forms of microcirculation disorders: arterial hyperemia, venous hyperemia, combined hyperemia, ischemia, and stasis [38]. The changes identified in this study in ME/CFS, including ME/CFS of post-COVID-19 nature, correspond to the hyperemic form of microcirculation disorders, which is characterized by increased blood flow into the mi- crocirculatory bed. It is distinguished by a significant increase in the number of functioning capillaries, an increase in tortuosity, vasodilation, and an increase in the permeability of the vascular wall. This form of microcirculation disorder is usually observed in acute inflammatory response or other conditions of decreased systemic vasoconstriction.

The state of microcirculation in ME/CFS, which developed before the COVID-19 pandemic, and ME/CFS of post-COVID-19 nature, differed only in terms of vascular re-sistance. Bond et al. showed that chronic oxidative stress could contribute significantly to the development of ME/CFS symptoms due to the development of endothelial dysfunc-tion [39]. The relationship between chronic inflammatory processes and increased arterial tion [39]. The relationship between chronic inflammatory processes and increased arterial stiffness is well-known [40]. An increase in vascular resistance in cohort 1 compared to stiffness is well-known [40]. An increase in vascular resistance in cohort 1 compared to cohort 2 may reflect the contribution of the chronic inflammatory process of a long course to microcirculation disorders and suggests the existence of long-term consequences of ME/CFS, in particular, an increased risk of cardiovascular diseases.

So, they conclude that there is congestion of the tissue with blood in both ME/CFS and post-Covid ME/CFS. They suggest the increased vascular resistance found in ME/CFS might be a product of the time chronic inflammatory processes have existed.
 
So, they conclude that there is congestion of the tissue with blood in both ME/CFS and post-Covid ME/CFS. They suggest the increased vascular resistance found in ME/CFS might be a product of the time chronic inflammatory processes have existed.

I am afraid it is just a word salad, @Hutan.
Anyone familiar with the clinical pathology of inflammation can see that they do not actually think through what they are saying.

If there is inflammation with increased flow the bit goes pink and warm - you can see it and feel it.
I haven't even worked out which bit of the person they are 'measuring'.
 
I get the impression that this is a team of people, probably some of whom have personal experience of ME/CFS, trying to fight for recognition in a society that, like most places, has dismissed ME/CFS as psychosomatic and just a version of depression. In that context, it's not surprising that anything remotely looking like evidence would be reported with enthusiasm. We've seen worse efforts to investigate and describe ME/CFS.

There is evidence that the two-day cardiopulmonary exercise test objectively measuring PEM makes it possible to distinguish ME/CFS patients from healthy individuals [29], which is of great importance in the absence of reliable laboratory biomarkers of ME/CFS. Deterioration of the patient’s condition after physical activity should serve as a warning for medical doctors against recommending ME/CFS patients increase the level of physical activity without careful supervision by a rehabilitation specialist.

Our data, therefore, not only agree with the concept of ME/CFS as a disease with neuroimmune pathogenesis but also allow us to make assumptions about approaches to diagnosis and treatment of this disease, as well as the most effective organization the patient care in ME/CFS, which optimally should be provided by neurologists.
 
I haven't even worked out which bit of the person they are 'measuring'.
Right forearm
we investigated forearm blood flow in the participants with «LASMA MC-1» peripheral blood and lymph flow laser diagnostic complex (LASMA LLC, Russia). Participants were examined once, with the diagnostic probe placed on the external surface of the right forearm for 2 min.
 
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