Small Fiber Neuropathy and SARS‐CoV‐2 Infection. Another piece in the long COVID puzzle?

Following the unprecedented worldwide impact on global health caused by the outbreak of the severe acute respiratory syndrome– coronavirus-2 (SARS-CoV-2) pandemic, further concern was raised by observing that coronavirus disease-2019 (COVID-19) additionally entailed a constellation of long-term symptoms. Long-term manifestations are in part directly related to sequelae of major organ damage in the acute phase (mainly lung fibrosis and cardiovascular complications, including stroke), and to post–intensive care syndrome. However, in many patients, a more elusive complex of persisting or newly developing symptoms is seen, not necessarily related to the severity of acute disease, collectively designated as “long COVID” or “post-COVID” syndrome. Patients with long COVID have a wide range of symptoms, including fatigue and exertional intolerance, chest pain, dyspnea even with preserved lung function, orthostatic malaise and lightheadedness, palpitations, “brain fog,” pain, anosmia and ageusia, headache, sleep difficulties, and gastrointestinal dysfunction, vastly differing between individuals, and likely caused by several different mechanisms. The pathophysiology has been regarded as resulting from the interaction of several factors. A rapid overproduction of cytokines and immune cell hyperactivation, together termed the cytokine storm, persistence of chronic inflammation or immune response/autoantibody generation, latent, chronic SARS-CoV-2 infections of extrapulmonary tissues, deconditioning, and psychological issues, may contribute in different measures to the long COVID syndrome, with the clinical picture likely depending on the relative predominance of these factors. Symptoms of lightheadedness, orthostatic intolerance, palpitations, and gastrointestinal dysfunction suggest dysautonomia, which has been confirmed by abnormal autonomic function tests in several long COVID patients. Some factors related to SARS-CoV-2 infection, such as deconditioning, weight loss, and hypovolemia, can favor the occurrence of autonomic symptoms, as well as anxiety and insomnia, caused by infection itself or disease-related measures such as quarantining, possibly leading to a hyperadrenergic state. Dysautonomia may originate at different levels, and localization to central or peripheral nervous system autonomic pathways cannot always be determined with certainty. The report of pain and dysesthesias in some long COVID patients with dysautonomia would suggest that symptoms are primarily related to involvement of small nerve fibers. Sudomotor dysfunction, supportive of autonomic neuropathy, has been reported in patients recovered from COVID-19. A number of long COVID patients present with postural orthostatic tachycardia syndrome, a phenotype often associated with small-fiber neuropathy (SFN). The article by Abrams and colleagues in this issue of the Journal seems to close the loop, reporting a series of patients with sensory SFN in association with SARS-CoV-2 infection, some of whom also had autonomic symptoms and abnormal quantitative sudomotor axon reflex tests (QSART). SFN was confirmed by abnormal skin biopsy in six patients and abnormal QSART in one, whereas the other six patients with suggestive symptoms had negative skin biopsies. Almost all patients developed sensory symptoms 2 weeks to 2 months after the infection, and had mild or asymptomatic COVID-19, confirming that the occurrence of long COVID manifestations is unrelated to the severity of infection. Thus, a subset of long COVID patients may have SFN, with a spectrum of small-fiber involvement ranging from autonomic manifestations to painful sensory symptoms, as already observed in other SFN entities. This observation raises some questions, starting with the establishment of a causal link between SARSCoV-2 infection and SFN. Abrams and colleagues argue that SFN appeared strongly associated to COVID-19 in their patients, who had no neurological symptoms before the viral infection; in other observations, mild or subclinical pre-existing SFN was exacerbated or unmasked by SARS-CoV-2 infection. As for possible pathogenic mechanisms, a postinfectious autoimmune neuropathy limited to small fibers seems likely, and consistent with the time interval between infection and onset of SFN symptoms. Other potential, yet unlikely, mechanisms include direct viral invasion, with lingering virus, possibly in the dorsal root ganglia neurons, that express the SARS-CoV-2 receptor angiotensin-converting enzyme 2, or cytokine-mediated small-fiber damage ensuing from the cytokine storm. Abrams and colleagues comment on the SFN pattern, that was apparently length-dependent based on the gradient of IENF loss, although a non–length-dependent (NLD) distribution of symptoms was seen in some patients. This point remains controversial, in the absence of definite NLD-SFN criteria, and deserves further study because of possible pathophysiological implications, considering that NLD-SFN is often autoimmune, and related to primary damage at the dorsal root ganglia level. The small sample size of SFN patients—a major limitation of the study—makes it difficult to quantify the actual impact of SFN in the setting of the increasingly large population of long COVID patients. SFN in association with long COVID may be underestimated, as diagnosis is difficult when the presentation is atypical, even more so in consideration of pandemic restrictions to the health-care system. A study of a cohort of long COVID patients using corneal confocal microscopy—a proposed SFN biomarker—demonstrated a significant loss of corneal small nerve fibers consistent with SFN, supporting the idea that the Received: 20 December 2021 Revised: 4 January 2022 Accepted: 5 January 2022