Central sensitization in long COVID: Associations with autonomic symptom burden, cerebral hypoperfusion, and neuroinflammation.

BACKGROUND

The mechanisms driving the broad spectrum of Long COVID symptoms-such as fatigue, brain fog, pain, and dysautonomia-remain uncertain. This study investigated central sensitization (CS) as a potential contributor to symptom burden in patients with Long COVID. We aimed to examine its association with symptom severity, as well as objective cerebrovascular, autonomic, and inflammatory markers.

METHODS

A total of 169 consecutive patients with Long COVID referred for evaluation of orthostatic intolerance underwent assessment using the Central Sensitization Inventory, symptom burden surveys (autonomic: COMPASS-31; sensory: NTSS-6; global health: PROMIS), autonomic function testing (deep breathing, the Valsalva maneuver and head-up tilt test with transcranial Doppler and capnography monitoring), and skin biopsies for small-fiber assessment.

RESULTS

CS was present in 81% of participants. Patients with CS were more often female (79.6% vs. 53.1%, p = 0.004) and had higher rates of anxiety, depression, fibromyalgia and headaches, as well as a significantly greater autonomic, sensory and global health symptom burden (all p < 0.001). Compared with patients without CS, they also exhibited a greater decline in orthostatic cerebral blood flow velocity (-25.53% ± 11.19 vs. -22.09% ± 10.53, p = 0.038) and higher interleukin-6 levels (p = 0.041). Autonomic failure, most commonly of mild grade, occurred at similar frequency in both groups (84.7% vs. 84.4%, p = 0.999). Skin biopsies demonstrated a comparable prevalence of abnormal findings in both groups (50.8% vs. 52.0%, p = 0.999).

CONCLUSION

Central sensitization appears highly prevalent among patients with Long COVID and may contribute to their multisystem symptomatology. Cerebral hypoperfusion, and neuroinflammation may constitute pathophysiological mechanisms underlying central sensitization in this population.