Autonomic small fiber involvement in painful long COVID: a histological and clinical study, 2026, Falco et al.

SNT Gatchaman

SNT Gatchaman

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Autonomic small fiber involvement in painful long COVID: a histological and clinical study
Falco, Pietro; Galosi, Eleonora; Litewczuk, Daniel; Evangelisti, Enrico; Di Stefano, Giulia; Arendt-Nielsen, Lars; Truini, Andrea; Leone, Caterina Maria

BACKGROUND
Despite growing recognition of painful long COVID syndrome as a chronic neurological condition marked by pain and autonomic symptoms, the precise contribution of autonomic small fiber involvement is still not well characterized and understood. In this retrospective study, we aimed to identify autonomic small fiber involvement in patients with painful long COVID syndrome by analyzing skin biopsy data. We used nerve fiber density in the piloerector muscles (PMNFD) and sweat glands (SGNFD) as the primary histological outcomes of autonomic innervation.

METHODS
We reviewed skin biopsy samples from 50 patients with painful long COVID syndrome and included 31 patients with available PMNFD and SGNFD data for analysis. PMNFD and SGNFD were compared with an age- and sex-matched healthy control group (n = 42). To evaluate whether autonomic involvement was independent of somatic nerve fiber reduction, a subgroup analysis was performed in patients with normal intraepidermal nerve fiber density (IENFD) (n = 23). Correlations between histological findings and autonomic symptoms, assessed with the COMPASS-31 questionnaire, were also analyzed.

RESULTS
Piloerector muscle nerve fiber density and SGNFD were significantly reduced in patients with long COVID compared with controls, both in the full sample (p = 0.0135; p < 0.0001) and in the subgroup with normal IENFD (p = 0.0003; p = 0.0005). Neither PMNFD nor SGNFD correlated with COMPASS-31 scores (p = 0.27; p = 0.46) and no association with disease onset, duration and COVID-19 severity was found.

CONCLUSION
These findings provide histological evidence that autonomic small fiber damage is a prominent and measurable feature of painful long COVID syndrome. Importantly, this pathology was also observed in patients with preserved IENFD, indicating that autonomic involvement may occur independently of somatic small fiber loss.

Web | DOI | PDF | Frontiers in Human Neuroscience | Open Access
 
The p-values seem impressive but the graphs show a lot of overlap:

figure 2
Four scatter plots comparing data between two groups: (A) shows distal PMNFD per mm between patients and controls, indicating higher values for controls. (B) shows distal SGNFD scores, with higher scores for controls. (C) presents distal PMNFD per mm for patients with normal IENFD versus controls, with controls having higher values. (D) displays distal SGNFD scores for patients with normal IENFD compared to controls, with controls again having higher scores. Each plot highlights statistically significant differences with an asterisk.
Figure 2. Reduced PMNFD and SGNFD in patients with long COVID compared to controls. (A) Individual values of PMNFD of all patients versus controls; (B) mean and standard deviation of SGNFD of all patients versus controls; (C) individual values of PMNFD of patients with normal IENFD versus controls; (D) mean and standard deviation of SGNFD of patients with normal IENFD versus controls. *p < 0.05.
 
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