Immune correlates underlying Small Fiber Neuropathy presenting as Vaccine-associated Post-Acute SARS-Coronavirus Syndrome

Alessandro Limongelli¹Federica Bozzano²Alireza Hajabbas Farshchi³Margherita Bellucci⁴Martina Bavastro⁵Chiara Castellano²Francesca Antonini⁶Alex Incensi⁷Giampaola Pesce²Maria Pia Giannoccaro⁷Antonio Uccelli²Genny Del Zotto⁶LORENZO MORETTA⁸VIncenzo Donadio⁷Luana Benedetti²Andrea De Maria^1*

• ¹Department of Health Sciences, University of Genoa, Genoa, Italy
• ²IRCCS Ospedale Policlinico San Martino, Genoa, Italy
• ³Department of Experimental Medicine, University of Genoa, Genoa, Italy
• ⁴Universita degli Studi di Genova Dipartimento di Neuroscienze Riabilitazione Oftalmologia Genetica e Scienze Materno-Infantili, Genoa, Italy
• ⁵Università degli Studi di Genova, Dipartimento di scienze della salute, Genoa, Italy
• ⁶Istituto Giannina Gaslini, Genoa, Italy
• ⁷Universita degli Studi di Bologna, Bologna, Italy
• ⁸Ospedale Pediatrico Bambino Gesu IRCCS, Rome, Italy

Abstract Background:A spectrum of adverse events overlapping with Post-acute Sequelae of SARS-CoV-2 infection (PASC) occurs in some patients following SARS-CoV-2 vaccination including small fiber neuropathy (SFN) and cognitive symptoms. Aims:Accruing information regarding disease course and immune response imbalances in these patients. Methods:We studied 71 previously healthy patients with neurological symptoms following SARS-CoV-vaccination. All had negative neurological workup for central/peripheral involvement (MR, EMG/EN). Cutaneous biopsy (21pts.) and peripheral blood sampling (20pts) were performed for anti-idiotype Ab analysis (ACE-2,NRP-1) (ELISA, IF) and for Flowcytometric analysis. ResultsParesthesia, cognitive impairment and autonomic symptoms agreed with SFN international definition. Comparative differences included abrupt onset, presence of simultaneous diverse paresthesia across multiple body regions frequently affecting the facial and cervical regions (44%) and the trunk (26%), associated to dysautonomia. Median time from vaccination to symptom manifestation was 3 days (mean±SD: 8.76±17.4 days). Symptom severity was still high (5.9±1.9 mean+SD) at the time of evaluation and sampling, (382±133 days from onset. Reduced small fiber density was observed in 19/21 biopsies. Anti-ACE-2 antibodies in 9/71pts. (12%) and 4/19 (21%) vaccinated HD sera and NRP-1 reactivity in 14/71 (20%) patient and 1/19 (5%) HD sera were not significantly increased. Peripheral NKG2D+CD8+ and NKG2D+DNAM-1+CD4+ T-cells were increased. Circulating inflammatory CD34+ cells were increased and generated in vitro a prevalence of NKG2D+DNAM-1+ T-cells. ConclusionPASC-vac SFN is associated with persistent immune imbalances common to other immune-mediated diseases. Additional effort to identify immune mechanisms unleashing PASC-vac SFN will contribute to modulate future early interventions for these patients and refine vaccine design.