{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T22:42:26Z","timestamp":1789512146313,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,2]],"date-time":"2025-02-02T00:00:00Z","timestamp":1738454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Post-acute sequelae of COVID-19 (PASC) syndrome is considered an emergent and diffuse multidisciplinary problem. Compelling evidence suggests that COVID-19 increases symptoms of pre-existent small fiber neuropathy (SFN) and might trigger de novo onset of SFN. In this systematic review, for the first time, we provide a comprehensive overview of the clinical and diagnostic features of PASC-SFN, including the accompanying disorders, disease evolution, and possible treatments, described in the recent literature. Following infection, many patients reported a wide range of symptoms and complications, not self-limiting and independent from previous infection severity. SFN begins more frequently with distal limb burning pain and numbness, which accompany other dysautonomia, cognitive, visual, and osteoarticular disorders involving multiple organ systems. In an initial diagnostic suspicion, some tests might be useful as complementary examinations, such as nerve quantitative sensory testing, electromyography, and optic nerve tomography. Otherwise, definite diagnosis is reached with skin biopsy as the gold standard, along with corneal in vivo microscopy when ocular discomfort is present. Being a long-term condition, multiple and dissimilar symptomatic and disease-modifying drugs were employed for the treatment of this condition with the achievement of partial results, including steroids, pregabalin, gabapentin, duloxetine, vitamins, homotaurine and phosphatidylserine, alpha lipoic acid, immunosuppressants, and intravenous immunoglobulin therapy. PASC-SFN is a complex emerging disease and extremely challenging for physicians. At present, the only feasible management of PASC-SFN is represented by a multidisciplinary tailored approach, with future definitive protocols for diagnosis and treatment deemed essential.<\/jats:p>","DOI":"10.3390\/microorganisms13020328","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T08:47:57Z","timestamp":1738572477000},"page":"328","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Post-COVID-19 Small Fiber Neuropathy as a New Emerging Quality of Life-Threatening Disease: A Systematic Review"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6874-4941","authenticated-orcid":false,"given":"Francesca","family":"Bandinelli","sequence":"first","affiliation":[{"name":"Rheumatology Department, Santa Maria Nuova Hospital, Usl Tuscany Center, 50122 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0906-4647","authenticated-orcid":false,"given":"Marco","family":"Di Carlo","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Clinical and Molecular Sciences, Universit\u00e0 Politecnica of Marche, Carlo Urbani Hospital, Jesi, 60035 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia Alba","family":"Colantuono","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Health Sciences, University of Florence, 50125 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0201-1227","authenticated-orcid":false,"given":"Filippo","family":"Nozzoli","sequence":"additional","affiliation":[{"name":"Section of Pathological Anatomy, Department of Health Sciences, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fausto","family":"Salaffi","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Clinical and Molecular Sciences, Universit\u00e0 Politecnica of Marche, Carlo Urbani Hospital, Jesi, 60035 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Chiocchetti","sequence":"additional","affiliation":[{"name":"Neurology Department, San Giovanni di Dio Hospital, Usl Tuscany Center, 50143 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Nucci","sequence":"additional","affiliation":[{"name":"Histopathology and Molecular Diagnostics, Careggi University Hospital, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3755-8802","authenticated-orcid":false,"given":"Alessandra","family":"Mastricci","sequence":"additional","affiliation":[{"name":"Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Gherardi","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Health Sciences, University of Florence, 50125 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3956-8480","authenticated-orcid":false,"given":"Mirko","family":"Manetti","sequence":"additional","affiliation":[{"name":"Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102","DOI":"10.55563\/clinexprheumatol\/r0kho4","article-title":"Neuropathic pain features suggestive of small fibre neuropathy in fibromyalgia syndrome: A clinical and ultrasonographic study on female patients","volume":"39","author":"Cesaroni","year":"2021","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_2","first-page":"1141","article-title":"Fibromyalgia: One year in review 2024","volume":"42","author":"Bianchi","year":"2024","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Di Carlo, M., Di Battista, J., Cipolletta, E., Okano, T., Chiorrini, R., Smerilli, G., Bandinelli, F., Filippucci, E., and Salaffi, F. (2024). Is Active Synovitis of Metacarpophalangeal Joints a Neuropathic Condition in Rheumatoid Arthritis Patients? Results from an Ultrasound Study of Palmar Digital Nerves. J. Clin. Med., 13.","DOI":"10.3390\/jcm13061599"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"154","DOI":"10.2174\/1573397114666180806142814","article-title":"The Effect of Neuropathic Pain Symptoms on Remission in Patients with Early Rheumatoid Arthritis","volume":"15","author":"Salaffi","year":"2019","journal-title":"Curr. Rheumatol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1007\/s00415-022-11431-1","article-title":"Clinical and paraclinical features of small fiber neuropathy in Sj\u00f6gren\u2019s syndrome","volume":"270","author":"Seeliger","year":"2023","journal-title":"J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s42358-020-00133-9","article-title":"Small fiber neuropathy and related factors in patients with systemic lupus erythematosus; the results of cutaneous silent period and skin biopsy","volume":"60","author":"Tekatas","year":"2020","journal-title":"Adv. Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e192","DOI":"10.1016\/S1473-3099(20)30483-7","article-title":"A Minimal Common Outcome Measure Set for COVID-19 Clinical Research","volume":"20","author":"Marshall","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_8","unstructured":"(2021, October 01). World Health Organization\u2014A Clinical Case Definition of Post COVID-19 Condition by a Delphi Consensus. Available online: https:\/\/www.who.int\/publications\/i\/item\/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.jiph.2022.06.013","article-title":"Persistent neurological manifestations in long COVID-19 syndrome: A systematic review and meta-analysis","volume":"15","author":"Pinzon","year":"2022","journal-title":"J. Infect. Public Health"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/s41591-021-01283-z","article-title":"Post-acute COVID-19 syndrome","volume":"27","author":"Nalbandian","year":"2021","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bandinelli, F., Pagano, M., and Vallecoccia, M.S. (2023). Post-COVID-19 and Post-COVID-19 Vaccine Arthritis, Polymyalgia Rheumatica and Horton\u2019s Arteritis: A Single-Center Assessment of Clinical, Serological, Genetic, and Ultrasonographic Biomarkers. J. Clin. Med., 12.","DOI":"10.3390\/jcm12247563"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"120490","DOI":"10.1016\/j.jns.2022.120490","article-title":"Long-COVID phenotypes and small fiber neuropathy","volume":"444","author":"Gemignani","year":"2023","journal-title":"J. Neurol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1097\/j.pain.0000000000003259","article-title":"Small fibre neuropathy frequently underlies the painful long-COVID syndrome","volume":"165","author":"Falco","year":"2024","journal-title":"Pain"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bandinelli, F., Nassini, R., Gherardi, E., Chiocchetti, B., Manetti, M., Cincotta, M., Nozzoli, F., Nucci, E., De Logu, F., and Pimpinelli, N. (2024). Small Fiber Neuropathy Associated with Post-COVID-19 and Post-COVID-19 Vaccination Arthritis: A Rare Post-Infective Syndrome or a New-Onset Disease?. J. Pers. Med., 14.","DOI":"10.3390\/jpm14080789"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e200244","DOI":"10.1212\/NXI.0000000000200244","article-title":"Case-Control Study of Individuals with Small Fiber Neuropathy After COVID-19","volume":"11","author":"McAlpine","year":"2024","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1136\/bjophthalmol-2021-319450","article-title":"Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID","volume":"106","author":"Bitirgen","year":"2022","journal-title":"Br. J. Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3728","DOI":"10.1093\/brain\/awz333","article-title":"Diagnostic criteria for small fibre neuropathy in clinical practice and research","volume":"142","author":"Devigili","year":"2019","journal-title":"Brain"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1111\/j.1529-8027.2010.00271.x","article-title":"Intraepidermal nerve fiber density at the distal leg: A worldwide normative reference study","volume":"15","author":"Lauria","year":"2010","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/ana.26268","article-title":"Novel Autoantibodies in Idiopathic Small Fiber Neuropathy","volume":"91","author":"Chan","year":"2022","journal-title":"Ann. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Nunez-Castilla, J., Stebliankin, V., Baral, P., Balbin, C.A., Sobhan, M., Cickovski, T., Mondal, A.M., Narasimhan, G., Chapagain, P., and Mathee, K. (2022). Potential Autoimmunity Resulting from Molecular Mimicry between SARS-CoV-2 Spike and Human Proteins. Viruses, 14.","DOI":"10.3390\/v14071415"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6627","DOI":"10.1007\/s10072-022-06423-y","article-title":"Network autonomic analysis of post-acute sequelae of COVID-19 and postural tachycardia syndrome","volume":"43","author":"Novak","year":"2022","journal-title":"Neurol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Talotta, R. (2023). Molecular Mimicry and HLA Polymorphisms May Drive Autoimmunity in Recipients of the BNT-162b2 mRNA Vaccine: A Computational Analysis. Microorganisms, 11.","DOI":"10.3390\/microorganisms11071686"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"106908","DOI":"10.1016\/j.infsof.2022.106908","article-title":"Successful combination of data base search and snowballing for identification of primary studies in systematic literature studies","volume":"147","author":"Wohlin","year":"2022","journal-title":"Inf. Softw. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s10072-020-04890-9","article-title":"Life with chronic pain during COVID-19 lockdown: The case of patients with small fibre neuropathy and chronic migraine","volume":"42","author":"Consonni","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100276","DOI":"10.1016\/j.ensci.2020.100276","article-title":"Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: A case report","volume":"21","author":"Novak","year":"2020","journal-title":"eNeurologicalSci"},{"key":"ref_26","first-page":"e43600","article-title":"Small Fiber Neuropathy After SARS-CoV-2 Infection and Vaccination: A Case-Based Comparison","volume":"15","author":"Schwartz","year":"2023","journal-title":"Cureus"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Panagiotides, N.G., Zimprich, F., Machold, K., Schlager, O., M\u00fcller, M., Ertl, S., L\u00f6ffler-Stastka, H., Koppensteiner, R., and Wadowski, P.P. (2023). A Case of Autoimmune Small Fiber Neuropathy as Possible Post COVID Sequelae. Int. J. Environ. Res. Public. Health, 20.","DOI":"10.3390\/ijerph20064918"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s10286-021-00803-8","article-title":"Autonomic dysfunction following COVID-19 infection: An early experience","volume":"31","author":"Shouman","year":"2021","journal-title":"Clin. Auton. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1186\/s12967-023-04678-3","article-title":"Dysautonomia and small fiber neuropathy in post-COVID condition and Chronic Fatigue Syndrome","volume":"21","author":"Azcue","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jtos.2021.10.010","article-title":"Small fiber neuropathy in the cornea of Covid-19 patients associated with the generation of ocular surface disease","volume":"23","author":"Barros","year":"2022","journal-title":"Ocul. Surf."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1159\/000524205","article-title":"Small-Fiber Neuropathy Possibly Associated with COVID-19","volume":"14","author":"Burakgazi","year":"2022","journal-title":"Case Rep. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Midena, E., Cosmo, E., Cattelan, A.M., Briani, C., Leoni, D., Capizzi, A., Tabacchi, V., Parrozzani, R., Midena, G., and Frizziero, L. (2022). Small Fibre Peripheral Alterations Following COVID-19 Detected by Corneal Confocal Microscopy. J. Pers. Med., 12.","DOI":"10.3390\/jpm12040563"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e1146","DOI":"10.1212\/NXI.0000000000001146","article-title":"Peripheral Neuropathy Evaluations of Patients with Prolonged Long COVID","volume":"9","author":"Oaklander","year":"2022","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1002\/mus.27458","article-title":"Small fiber neuropathy associated with SARS-CoV-2 infection","volume":"65","author":"Abrams","year":"2022","journal-title":"Muscle Nerve"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1167\/iovs.17-23342","article-title":"Corneal Nerve Fractal Dimension: A Novel Corneal Nerve Metric for the Diagnosis of Diabetic Sensorimotor Polyneuropathy","volume":"59","author":"Chen","year":"2018","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s42399-022-01167-4","article-title":"Post-acute sequelae of COVID-19 (PASC): A meta-narrative review of pathophysiology, prevalence, and management","volume":"4","author":"Munipalli","year":"2022","journal-title":"SN Compr. Clin. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Habat, S., Meiner, Z., Tsenter, J., Schwartz, I., and Portnoy, S. (2022). Correlations between Electro-Diagnostic Findings, the Severity of Initial Infection, and the Rehabilitation Outcomes among COVID-19 Patients. Biology, 11.","DOI":"10.3390\/biology11020277"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Chiaramonte, R., Romano, M., and Vecchio, M. (2020). A Systematic Review of the Diagnostic Methods of Small Fiber Neuropathies in Rehabilitation. Diagnostics, 10.","DOI":"10.3390\/diagnostics10090613"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Nolano, M., Tozza, S., Caporaso, G., and Provitera, V. (2020). Contribution of Skin Biopsy in Peripheral Neuropathies. Brain Sci., 10.","DOI":"10.3390\/brainsci10120989"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1111\/exd.14384","article-title":"A systematic review of the histopathologic survey on skin biopsies in patients with Corona Virus Disease 2019 (COVID-19) who developed virus or drug-related mucocutaneous manifestations","volume":"30","author":"Seirafianpour","year":"2021","journal-title":"Exp. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/mus.27245","article-title":"TS-HDS and FGFR3 antibodies in small fiber neuropathy and Dysautonomia","volume":"64","author":"Trevino","year":"2021","journal-title":"Muscle Nerve"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1097\/CND.0000000000000485","article-title":"Effectiveness of IVIG on Non-Length-Dependent Skin Biopsies in Small Fiber Neuropathy with Plexin D1, Trisulfated Heparin Disaccharide, and Fibroblast Growth Factor Receptor 3 Autoantibodies","volume":"25","author":"Zeidman","year":"2024","journal-title":"J. Clin. Neuromuscul. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/j.1085-9489.2006.00062.x","article-title":"Acute steroid responsive small-fiber sensory neuropathy: A new entity?","volume":"11","author":"Dabby","year":"2006","journal-title":"J. Peripher. Nerv. Syst."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/2\/328\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:25:58Z","timestamp":1760027158000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/2\/328"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,2]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["microorganisms13020328"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms13020328","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,2]]}}}