Novak P;  Brigham and Women’s Hospital, Boston, Massachusetts, USA
Systrom DM; Witte A; Marciano SP; Felsenstein D; Milunsky JM;
Milunsky A; Krier J; Fishman MC

PLoS ONE [Electronic Resource]. 21(1):e0341278, 2026.

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 Women’s 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.