Guillain Barré syndrome and COVID-19: Possible role of the cytokine storm.

Dear Editor

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the global pandemic of coronavirus disease 2019 (COVID-19). A member of the β-coronavirus family, the SARS-CoV-2 predominantly targets the angiotensin-converting enzyme 2 (ACE2) receptor protein [1]. The receptor is expressed on a variety of cell types, including vascular and respiratory epithelium and alveolar monocytes. The SARS-CoV-2 augments a severe acute immune-response with a marked upsurge of pro-inflammatory cytokines, also known as the cytokine release storm (CRS), which is instrumental to the pathogenesis of COVID-19 [2]. Although the most serious manifestations of COVID-19 are pulmonary and neurological, both central and peripheral complications have been reported in 36% cases [3]. Several reports have described COVID-19 associated Guillain-Barré Syndrome (GBS) [[4], [5], [6]]. GBS can be associated with considerable morbidity and mortality due to rapidly progressive weakness of bulbar, limb and respiratory muscles [[4], [5], [6], [7]]. Herein, we briefly explore the role of COVID-19-mediated CRS, its possible association with GBS and therapeutic implications.

GBS is a heterogeneous disease with considerable clinical and phenotypic variation. The two major types include acute inflammatory demyelinating polyneuropathy (AIDP - demyelinating) and acute motor axonal neuropathy (AMAN-axonal), where the immunologic processes target the myelin or the axons, respectively. In about 2/3rd of cases, GBS is preceded by a bacterial or viral infection of the respiratory or gastrointestinal tract with Campylobacter jejuni (26–65%) [8], cytomegalovirus (10–15%), Epstein–Barr virus (8–10%) being the most common pathogen. Other agents include mycoplasma pneumonia, Haemophilus influenzae, and influenza A virus [9]. Antecedent infection with hepatitis E virus has been identified as a potential trigger of GBS in up to 5 to10% patients [10,11]. Further, previous outbreaks of the Zika virus resulted in an upsurge in the incidence of GBS that was more severe [12]. About 50–85% of patients with GBS or its variants have antiganglioside antibodies in their sera [13,14]. Gangliosides are sialylated glycosphingolipids found abundantly in various nervous tissues and the antibodies develop post-infection due to shared epitopes between the gangliosides and the infectious agent. In GBS, this phenomenon of molecular mimicry leads to binding of the antibody to nerves causing impaired conduction of impulses and axonal degeneration.

Recent reports show that GBS associated with COVID −19 has multiple distinctive features. As compared to the typical “post-infectious” course in the classical form, the GBS associated with COVID-19 presents as an “acute para-infection” as almost all reported cases have had acute onset within days of onset of viral infection, mostly within the first few days. The disease typically follows a florid course leading to flaccid limb paralysis and respiratory failure requiring ventilatory support within days of onset. Both axonal and demyelinating variants have been reported, more so the former. In all cases, the cerebrospinal fluid (CSF) shows elevated protein levels with few inflammatory cells. The CSF PCR essay for COVID −19 virus has consistently been negative and MRI, when done, did not show enhancement of the nerve roots in many cases. Importantly, no reported patients showed rise in the serum titers of antiganglioside antibodies. Finally, therapeutic response to conventional therapies, both intravenous immunoglobulin (IVIg) or plasma exchange, in the GBS associated with COVID-19 has been suboptimal with outcomes being worse as compared to classical GBS.

The differences in COVID-19 associated GBS with GBS in the classical form are intriguing. Direct damage to the nerve roots by the COVID-19 virus, as seen with CMV and VZV infections, appears unlikely as the CSF lacks signs of infection, the CSF PCR is negative for the COVID −19 virus and the nerve root involvement is not always obvious on MRI. More likely the nerves/nerve roots are affected as part of systemic, acute, and severe dysimmune processes in association with widespread pulmonary and extra-pulmonary manifestations of COVID-19. This has been previously noted with Zika virus infection where the GBS occurs early during the course of the infective process and has a more rapid and severe course with distal demyelination of the nerves [15].

In COVID-19, the early CRS results in a surge of several cytokines including interleukin-1β (IL-1β), IL-6, IL-17, tumor necrosis factor-α (TNF- α), interferon-γ (IFN-γ) along with other chemokines [16], which are mediators of the widespread and severe damage culminating in multi-organ failure and death primarily associated with acute respiratory distress syndrome [17]. Many of the same cytokines have been implicated in the pathogenesis of classical GBS (see below) and it is likely that the early CRS in COVID-19 plays a pivotal role in the concurrent development of GBS and its rapid progression. This notion is further supported by the following known observations:

In experimental models of GBS i.e. experimental autoimmune neuritis (EAN) administration of recombinant IFN-γ has shown to worsen the condition, administration of a monoclonal antibody to IFN-γ suppresses the disease, and IFN-γ receptor deficient mice show milder disease than wild type [18].

Allelic polymorphism of TNF-α, crucial in macrophage signaling and Th1 pathway, is associated with AMAN susceptibility and possibly involved in GBS pathogenesis. Furthermore, it is endorsed by the elevated levels of TNF- α during the acute phase of GBS

Serum TNF-α levels are elevated during the acute phase of GBS, correlate with its clinical severity and decrease after treatment with IVIg or plasma exchange [18].

CSF levels of IFN-γ, IL-4, IL-17, and IL-22 are elevated in GBS [19,20]. IL-17 is implicated in myelin damage via Schwann cell mediated demyelination [21]. More importantly the CSF levels of both IL-17 and IL-22 correlate with severity of GBS on disability scale scores [22].

The Th1 and Th17-related cytokine levels in the blood, are significantly increased in GBS patients and the number of circulating Th17 cells and level of IL-17A decrease after treatment with IVIg [20].

The COVID-19-mediated CRS causes a surge in the brain of IL-2, IL-7, IFN-γ, macrophage inflammatory protein 1-α, and TNF-α, leading to hyperinflammation, severe encephalopathy and stroke [23].

These observations have important clinical implications for treatment of COVID-19 associated GBS, particularly during the early phase. Patients presenting with the typical GBS and its variants respond favorably to IVIg and plasma exchange but not to corticosteroids. However, in the case of GBS associated with COVID-19, and its possible association with CRS, the role of steroids has not been determined. Indeed, corticosteroids are reported to be effective in the management of the pulmonary and extra-pulmonary manifestations of COVID-19, if used early in the course of the disease [24]. Likely, this is due to their ability to modulate a number of cytokines i.e. IL-1, IL-6, IL-8, IL-12 and TNFα. Low dose corticosteroids have also been used previously, in the closely related SARS-CoV outbreaks [25,26]. Untill more data becomes available in patients with COVID-19 associated GBS, it may be prudent to keep concurrent steroids on board along with other conventional therapies.

Declaration of Competing Interest

None.