The Pathological Culprit of Neuropathic Skin Pain in Long COVID-19 Patients: A Case Series

Abstract

Cutaneous neurosensory symptoms have become increasingly reported findings in COVID-19; however, these virus-related manifestations are largely overlooked, and their pathology is poorly understood. Moreover, alterations of skin sensibility currently recognize no clear histopathology substrate. The purpose of this study was to provide pathology evidence of neurosensory skin system involvement in COVID-19 patients complaining of subjective neurological symptoms affecting the skin. Out of 142 patients, six long COVID-19 cases complaining of cutaneous subjective neurological symptoms assessed on an NTSS-6 questionnaire underwent histopathological and immunohistochemical analyses of skin areas affected by paroxysmal diffuse burning and itching sensations. Two patients also performed electroneurography examination. The histology investigation showed hypertrophic glomus vascular bodies with hypertrophic S100+ perineural sheath cells and adjacent hypertrophy of the nerve branches associated with increased basophil polysaccharide matrix. Electroneurography revealed disturbances of A-delta and C dermal neuronal fibers. The main limitation of this study consisted of a limited number of skin biopsy samples, requiring further investigation. Histopathology findings are consistent with hypertrophy of nerve endings, suggesting a condition such as “dermal hyperneury”, a recently reported small nerve hypertrophy condition affecting sensory C fibers. Such a neuropathic basis could explain dysesthesia experienced by the patients, as previously described in postherpetic neuralgia.

Long COVID in Children, Adults, and Vulnerable Populations: A Comprehensive Overview for an Integrated Approach

“…Interestingly, in a recent study conducted by Grieco et al [114], the authors investigated cutaneous subjective neurologic symptoms (sNSs) in both subjects with acute COVID-19 and long COVID syndrome. Six long COVID patients suffering from cutaneous sNSs, evaluated through the Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire, underwent a histopathological examination of cutaneous areas affected by paroxysmal diffuse burning and itching sensations.…”

“…In the above-mentioned study, histopathological analyses showed the hypertrophy of dermal nerve fibers resembling dermal hyperneury, a rare form of small nerve hypertrophy that affects sensory C fibers [115], and these findings could explain the dysesthesia experienced by the studied patients. In addition, electroneurography was also performed on two patients, revealing altered dermal A delta and C neuronal fibers, although it remains to be clarified whether this was due to the direct action of the virus on the terminal nerve fibers or other indirect mechanisms [114].…”

Long COVID, the Brain, Nerves, and Cognitive Function

“…Although neuropathic pain can have central or peripheral etiologies, neuropathic pain persisting for 3 months after acute COVID-19 infection has been attributed to peripheral neuropathy [ 135 , 136 , 137 , 138 ]. Although both small and large fiber nerves are affected, recent evidence has shown that it is the small diameter, lightly myelinated or unmyelinated nerves that are most susceptible to damage [ 139 ]. The lack of myelination leaves axons subject to local stressors, including those produced by immune dysregulation.…”

Telogen effluvium in SARS‐CoV‐2 infection: Histological aspects

“…It is a sensory C-fibre phenomena seen in chronic COVID neuropathic skin pain (Figure 2). 5 Impairment of the peripheral nervous system in COVID is extremely common as it hosts ACE-2 receptors.…”