Increasing associations of long-COVID with small-fiber neuropathy

SARS-CoV2 infections leave 7.8–17.0% of patients with symptoms lingering for 12+ weeks.²³ Yet the causes of long-COVID (LC aka post-acute sequelae of COVID-19) remain unknown in pandemic year 4, precluding optimal treatment. Medical specialists have been working overtime to explicate specific LC symptoms, including pain specialists. The most common LC symptoms are not pain, but rather impaired memory and cognition (“brain fog”) and premature exertional fatigue, sometimes with shortness of breath and aching muscles.²³ Others report chronic headaches. A few report neuropathic pain consistent with small-fiber peripheral neuropathy (SFN), and earlier LC case series documented high prevalences of SFN.^{1, 25, 28} However, the more common, non-painful symptoms of LC are associated with SFN in other ill-defined syndromes, attributed to damage to internal somatic and autonomic small-fibers.^{3, 9, 15, 17, 26} Even cognitive concerns, prevalent in SFN as well as LC,³⁴ have been attributed to altered small-fiber input into brain networks or disordered brain perfusion.¹⁶ A unifying pathophysiology in SFN seems to be reduced small-fiber activation of perivascular myocytes. This impedes directing blood to meet periodic increased demand,² and decreases peripheral vascular tone, impeding venous return to the heart and cardiac output.¹⁷

Now a new study from Falco et al. associates SFN with painful symptoms appearing within 0–2 months after start of SARS-CoV2 infections.¹⁰ The team analyzed clinical data, standardized patient questionnaires, quantitative sensory testing, nerve conduction study, and skin biopsies for SFN in 26 selected patients with painful LC. They did not ascertain standard clinical diagnoses, making their series hard to compare to other diagnosis-based cohorts, but nearly all in their LC cohort had widespread pain suggestive of SFN. Their study added rigor because it included two control groups: 33 LC-patients with the most common LC symptoms, premature fatigue and/or brain fog without chronic pain, plus 30 people without LC after SARS-CoV2 infections. Unfortunately, as they did not perform skin biopsies in their control groups, and patients with neuropathy diagnoses or risks were excluded, they could not document the prevalence of SFN in non-painful LC, nor calculate relative risks.

Their major finding was that 46% of their painful LC group had skin biopsy and/or quantitative sensory testing abnormalities consistent with SFN. The team also biopsied their painful-LC cohort at the standard upper thigh site 20 cm below the iliac crest in addition to the mandatory lower-leg site 5 cm above the lateral malleolus, demonstrating that more patients (42%) had proximal than distal (23%) neurite reductions. This suggests that LC-SFN is more often a non-length-dependent than distal-predominant neuropathy and the earlier distal-only biopsy studies may have underestimated the prevalence of SFN in LC. This was true in fibromyalgia, where distal-only biopsy studies identified ≈50% prevalence of SFN-diagnostic skin biopsies,^{15, 26} which 2-site biopsies raised to 63%.⁹ Thus, clinical biopsy testing for SARS-CoV2-incident SFN (and fibromyalgia) should include two-site biopsies to increase sensitivity.

This reported 46% prevalence of SFN in painful long-COVID is similar to prevalences of small-fiber pathology and SFN in other multi-symptom painful syndromes such as fibromyalgia and chronic fatigue/myalgic encephalomyelitis, highlighting the centrality of small-fiber pathology in these symptoms, regardless of how they are labeled.^{3, 9, 15, 17, 26} However, diagnosing SFN is not just a matter of semantic preference. Unlike syndromic labels, small-fiber neuropathy meets the requirements for a medical disease. It has a single unifying cellular pathology and pathophysiology, which permits objective confirmation and diagnostic criteria.¹¹ Test-confirmed diagnoses offers patients and clinicians stronger evidence-based medical frameworks than symptom-based syndromic labels. SFN has identifiable medical causes and mechanism-targeting and potentially disease-modifying treatments.(reviewed in²⁹) Identifying when chronic pain, intractable fatigue, post exertional malaise, and orthostatic intolerance are caused by misfiring and degenerating small-fiber neurites enables use of mechanism-targeting treatments more likely to improve health and functioning.¹⁸

But what causes small-fibers to malfunction and degenerate in long-COVID? This study excluded people with pre-existing chronic pain, fibromyalgia, neuro-diagnoses, and classic causes of neuropathy, precluding investigation of causality.¹⁰ Autopsies and other research have established that direct viral invasion into neurons is not the cause of post-COVID neuropathy, indeed most cases follow mild COVID.³³ Instead, considerable–albeit indirect–evidence links post-infectious and initially idiopathic SFN to dysimmunity. Clinical clues from other settings include high prevalences of comorbid autoimmune conditions (particularly Sjögren’s syndrome),²⁷ inflammatory markers,¹⁹ autoantibodies,^{4, 7} immunoglobulin deficiencies, and other B-cell disorders.^19–21 Circumstantial clues include sudden onset,^{6, 14, 30, 35} preceding infections, non-length-dependent presentations, SFN in otherwise healthy young adults and children, and responsiveness to immunotherapies.^{20, 27, 30, 31} The most direct proof that autoimmunity can cause acute and post-infectious SFN comes from identifying pathogenic nociceptor-targeting autoantibodies in rare patients.^{4, 7, 12, 14, 35} Post-infectious neuropathies are typically attributed to primed immunocytes mistargeting neuronal surface proteins (epitopes) and perhaps bound antibodies (anti-idiotypic binding). Guillain-Barré, which is easily diagnosed, was the first documented post-COVID neuropathy, but SFN may be the most prevalent post-COVID neuropathy.^{28, 32} Nociceptive small-fiber neurons are the primary expressors of ACE-2 and other SARS-CoV2 receptors in sensory ganglia, and small-fibers lack protective myelination and traffic with immunocytes, leaving them preferentially vulnerable dysimmunity.⁵

The implication is that some LC patients with confirmed SFN, like those described here, might respond to immunotherapies. These have risks and should only be prescribed to patients with apparently autoimmune SFN,¹³ but small case-series document short-term efficacy of corticosteroids and plasmapheresis in this specific context.^{14, 27, 30, 36} There are no clinical trials of long-term therapy, but many case series report efficacy and safety of repeated high-dose intravenous immunoglobulin (IVIg) treatment, including for post-COVID SFN,²⁰ and there is increasing use of IVIg for post-COVID neurological syndromes in general.^{22, 24} High-dose immunoglobulin therapy impedes B-cell activity by covering antigenic epitopes and binding pathogenic autoantibodies while impairing complement and cytokine pathways. NIH has funded phase 2 clinical trials of treatments for various long-COVID symptoms (https://trials.recovercovid.org/), and several are testing IVIg. Neither chronic pain nor SFN are primary outcomes so far. However, with 10% reported prevalence of neuropathic pain in patients with LC (95% CI: 5%−15%),⁸ and ≈50% prevalence of small-fiber neuropathy in painful long-COVID, is it time to consider clinical trials of IVIg for apparently autoimmune painful post-COVID SFN?