Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome, 2026, Novak, Systrom+

[SNT Gatchaman]

Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome
Peter Novak; David M Systrom; Alexandra Witte; Sadie P Marciano; Donna Felsenstein; Jeff M Milunsky; Aubrey Milunsky; Joel Krier; Mark C Fishman

INTRODUCTION
Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are relatively common and disabling multisystem disorders that share overlapping features, including post-infectious onset and similar clinical manifestations such as brain fog, fatigue, muscle pain, and dysautonomia with orthostatic intolerance. These similarities suggest that Long COVID and ME/CFS may share common pathophysiological mechanisms, though the underlying mechanisms remain poorly understood, partly due to the difficulty in quantifying many of the symptoms.

MATERIALS AND METHODS
This retrospective study evaluated Long COVID and pre-COVID ME/CFS patients who completed autonomic testing between 2018 and 2023 at the Brigham and Womens Faulkner Hospital Autonomic Laboratory. The evaluations included autonomic tests (Valsalva maneuver, deep breathing, tilt-table test, and sudomotor function) with capnography and transcranial Doppler monitoring of cerebral blood flow velocity (CBFv) in the middle cerebral artery, neuropathic assessment through skin biopsies for small fiber neuropathy (SFN), invasive cardiopulmonary exercise testing (ICPET), and laboratory analyses covering metabolic, inflammatory, autoimmune, and hormonal profiles.

RESULTS
A total of 143 Long COVID and 170 ME/CFS patients were analyzed and compared to 73 healthy controls and 290 patients with hypermobile Ehlers-Danlos syndrome (hEDS). Tests revealed extensive similarities between Long COVID and ME/CFS, including reduced orthostatic CBFv (92%/88% in Long COVID/ME/CFS), mild-to-moderate widespread autonomic failure (95%/89%), presence of SFN (67%/53%), postural tachycardia syndrome (POTS) (22%/19%), neurogenic orthostatic hypotension (15%/15%) and preload failure (96%/92%, assessed in 25/66 Long COVID/ME/CFS). Patients with hEDS exhibited more severe peripheral neurodegeneration compared to the other groups. Laboratory tests did not distinguish between the conditions.

CONCLUSION
Both Long COVID and ME/CFS demonstrate dysregulation in cerebrovascular blood flow, autonomic reflexes, and small fiber neuropathy, suggesting that these conditions may share a common underlying pathophysiology. However, differing distributions of findings in patients with hEDS raise the question of whether these conditions represent distinct but overlapping syndromes or reflect a shared underlying pathway. Further research is required to clarify the relationship between these conditions and the potential underlying pathophysiological mechanisms.

Web | DOI | PDF | PLOS ONE | Open Access

 

[Alinda]

I was expecting SFN to be high, but not that high!

 

[SNT Gatchaman]

Some top-line quotes —

Orthostatic lightheadedness was observed in >65% of patients, but orthostatic dyspnea was reported only in 21% of Long COVID patients, 37% of ME/CFS patients, and 28% of hEDS patients.

Tests revealed extensive similarities between Long COVID and ME/CFS, including reduced orthostatic CBFv (80%/92% Long COVID/ME/CFS), mild-to-moderate widespread autonomic failure (89%/95%)

Small fiber neuropathy affected ~80–90% of patients using combined morphological and functional criteria.

Deconditioning was defined as the predicted peak oxygen uptake < 85%, preload failure was defined as right atrial pressure < 6.5 mmHg

Preload failure was detected in 96% of Long COVID and 92.4% of ME/CFS patients. Deconditioning was present in 64% of Long COVID and ME/CFS patients.

cardiac output adjusted for BMI was similar between the groups.

Our study confirmed a high prevalence of central sensitization in Long COVID (78.1%), ME/CFS (85.4%), and hEDS (92.4%).

(See thread Establishing Clinically Relevant Severity Levels for the Central Sensitization Inventory)

Typically a reduction in orthostatic CBFv by 19% or more from the supine baseline is associated with symptoms of central nervous system dysfunction. Both our patient groups exceeded that level of decline (Long COVID −25% and ME/CFS −22%).

We were unable to find particular features in laboratory values that would differentiate the studied disorders. Most of the subjects had normal laboratory values, and abnormal results were found in a minority of patients. There were no differences between Long COVID and ME/CFS in inflammatory, autoimmune, adrenergic, and hormonal markers.

We were unable to detect hormonal changes indicative of adrenal or hypothalamic-pituitary-adrenal axis insufficiency, as evidenced by normal cortisol and ACTH levels across our studied groups.

Duration of the disease may affect the signature of ME/CFS, particularly the immunological profile which was not different between the groups. A greater prevalence of deconditioning, which would be expected with a longer-lasting ME/CFS, was also not detected in our study. Furthermore, autonomic failure was more severe in the Long COVID group, also speaking against the time effect.

 

[DHagen]

LC Criteria, pp. 3-4:

Long COVID diagnosis was based on the following: 1) Evidence of previous SARS-CoV-2 infection—established by a history of acute illness (characterized by fever, cough and malaise) and confirmed by a positive SARS-CoV-2 test (either antigen or polymerase chain reaction). 2) Symptoms linked to Long COVID. Long COVID is a heterogenous condition, and at the time the study was performed, the exact diagnostic criteria were still evolving [7]. Long COVID was defined as a constellation of persistent, relapsing or new symptoms after an acute infection [7,24]. These symptoms are brain fog, fatigue, smell/taste changes, post-exertional malaise, chronic cough, thirst, palpitations, dizziness, and gastrointestinal symptoms at variable combinations. The study included subjects who were infected during the pre-Delta era (before June 18, 2021), the Delta era (June 19, 2021 to December 18, 2021), and the Omicron era (after December 18, 2021) [25].

ME/CFS Criteria, p. 4:

The diagnosis of ME/CFS was based on myalgic encephalomyelitis international consensus criteria (ME-ICC) [26]
or newer National Academy of Medicine diagnostic criteria [27].

hEDS Criteria, p. 4:

Diagnosis of hEDS was based on the Beighton-Villefranche criteria for patients seen prior to 2017) [30], and on the
2017 international criteria thereafter [31]. All hEDS diagnoses and were made by genetic specialists (JK, AM, or JM).
The Beighton-Villefranche criteria do not distinguish between hEDS and hypermobile spectrum disorders, the latter being
considered a milder form of hEDS [31]. Therefore, diagnoses made prior to 2017 were retrospectively confirmed using the
updated international criteria.

Exclusion Criteria, p.4:

Exclusion criteria. We excluded patients with hEDS who had a concurrent diagnosis of chronic fatigue [19] or met the
diagnostic criteria for ME/CFS. Additionally, patients who did not complete or were unable to tolerate autonomic testing
were excluded

Spoiler: References

[7]
Thaweethai T, Jolley SE, Karlson EW, Levitan EB, Levy B, McComsey GA, et al. Development of a Definition of Postacute Sequelae of SARS-
CoV-2 Infection. JAMA. 2023;329(22):1934–46. https://doi.org/10.1001/jama.2023.8823 PMID: 37278994

[19]
Hakim A, De Wandele I, O’Callaghan C, Pocinki A, Rowe P. Chronic fatigue in Ehlers-Danlos syndrome-Hypermobile type. Am J Med Genet C
Semin Med Genet. 2017;175(1):175–80. https://doi.org/10.1002/ajmg.c.31542 PMID: 28186393

[24]
Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV, WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case
definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22(4):e102–7. https://doi.org/10.1016/S1473-3099(21)00703-9 PMID: 34951953

[25]
CDC. COVID Data Tracker. In: Centers for Disease Control and Prevention [Internet]. 2020 [cited 22 Aug 2024]. Available from: https://covid.cdc.gov/covid-data-tracker

[30]
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-
Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998;77(1):31–7. https://doi.org/10.1002/
(sici)1096-8628(19980428)77:1<31::aid-ajmg8>3.0.co;2-o

[31]
Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8–26. https://doi.org/10.1002/ajmg.c.31552 PMID: 28306229

 

[Sean]

I remain of the view that ME/CFS and a large fraction of the currently broadly defined LC are going to be the same disease.

 

[Eddie]

I haven't looked through the paper yet, but I think mechanisms of orthostatic intolerance is going to be key to this disease. Looking for differences between what is happening when lying down and when standing is something that needs more study.

 

[jnmaciuch]

I’m glad the paper included healthy controls. If the conclusion is that ME/CFS and LC don’t differ much from eachother across this battery of tests, I think it also has to be stated that neither group differs that much from healthy controls across all but maybe a few measures.

 

[Jonathan Edwards]

I don't think a retrospective review like this can be taken as reliable evidence of anything, sadly.
The patients studied will have been highly selected by referral routes and presenting symptoms that fit the clinic's interests. Rather than give figures for numbers claimed to have certain pathologies I think we need to see data plots. I think it would be very unwise to take these findings as representative of the diagnostic groups or as indicators of similar pathogenesis.

 

[neophyte32]

I don't think a retrospective review like this can be taken as reliable evidence of anything, sadly.
The patients studied will have been highly selected by referral routes and presenting symptoms that fit the clinic's interests. Rather than give figures for numbers claimed to have certain pathologies I think we need to see data plots. I think it would be very unwise to take these findings as representative of the diagnostic groups or as indicators of similar pathogenesis.

Oh dear! For once I found this study well-conducted, coherent with very interesting results.

 

[Turtle]

A question for members with more knowledge: Is the way the authors define deconditioning right?

Other researchers tried very hard to get rid of that term.

 

[EndME]

Maybe its just the way the data is presented but surely the SFN results are meaningless? I suspect that something similar might be true elsewhere, with practictionar bias being a problem. I don't think the healthy control group was of much use rather than just being used.

 

[hotblack]

Have they identified a commonality between LC and ME/CFS or a commonality between ill people, or as @Jonathan Edwards says a commonality between the patients that end up in their clinic?

I’d also like to understand more about these tests and their ability to distinguish between different diseases. Perhaps the reason this paper reports they cannot distinguish between LC and ME/CFS is because they cannot distinguish between LC and ME/CFS, not that they have identified any common underlying pathophysiology? Is this paper telling us what they haven’t been able to find more than what they have found?

We often hear of these sort of tests being used, they can ‘feel’ appropriate for what we experience, but do we have evidence of their diagnostic capability? I don’t know enough about them. Maybe others have experience of using these techniques?

 

[EndME]

Have they identified a commonality between LC and ME/CFS or a commonality between ill people, or as @Jonathan Edwards says a commonality between the patients that end up in their clinic?

I’d also like to understand more about these tests and their ability to distinguish between different diseases. Perhaps the reason this paper reports they cannot distinguish between LC and ME/CFS is because they cannot distinguish between LC and ME/CFS, not that they have identified any common underlying pathophysiology? Is this paper telling us what they haven’t been able to find more than what they have found?

We often hear of these sort of tests being used, they can ‘feel’ appropriate for what we experience, but do we have evidence of their diagnostic capability? I don’t know enough about them. Maybe others have experience of using these techniques?

As far as the SFN goes there doesn't seem to be any control so I don't think you can conclude that they identified anything common between certain illnesses or being ill. It more looks like they identified a group of doctors that'll count lines when paid to do so.

 

[Jonathan Edwards]

Note that the same authors wrote a paper:

Mismatch between subjective and objective dysautonomia​

In other words, retrospective assessment on clinical grounds is likely unreliable.

 

[Jonathan Edwards]

It more looks like they identified a group of doctors that'll count lines when paid to do so.

That would be a plausible interpretation.

 

[hotblack]

As far as the SFN goes there doesn't seem to be any control so I don't think you can conclude that they identified anything common between certain illnesses or being ill. It more looks like they identified a group of doctors that'll count lines when paid to do so.

Yeah.

Table 1 doesn’t have any of the lab tests for controls

Table 2 they have a subset of their patient reported symptoms for controls

Table 3 they have done all their suite of autonomic tests on controls

Table 5 no controls for invasive cardiopulmonary tests

 

[EndME]

Table 3 they have done all their suite of autonomic tests on controls

And without any blinding many of those observations are pointless, might as well not have had controls.

 

[Mij]

Conditions have phenotypes so we can't draw conclusions based on a selective group of patients.

I didn't have dysautonomia symptoms until a decade post ME viral onset. The orthostatic stress symptoms developed after reactivation of EBV and HHV6.

I've changed the language I use with my new GP b/c I don't have OI. My BP is always normal.