Introduction

Neurological complications of the novel coronavirus disease 2019 (COVID-2019) are increasingly reported and include both para-infectious manifestations (i.e., developing at the same time of the acute infection by the severe acute respiratory syndrome coronavirus [SARS-CoV-2]) and post-infectious disorders. The first category includes encephalopathy and stroke [1, 2], while delayed neurological complications are often immunotherapy-responsive, including steroid-sensitive encephalitis [3] and Guillain-Barré syndrome (GBS) [4]. However, the exact pathogenesis of these neuroimmune complications remains elusive, and it is also unknown whether a clinically mild or asymptomatic COVID-19 infection is sufficient to act as a trigger.

Herein, we report the clinical and immunological features in a case of SARS-CoV-2-induced GSB (Si-GBS).

Case report

A 53-year-old man presented with a 6-day history of lower limb paresthesia, followed by distal weakness, ataxia, and areflexia. The patient did not manifest fever, cough, diarrhea, nor fatigue in the 4 weeks prior to hospitalization. However, he reported a close contact with COVID-19-infected colleagues 17 days before the onset of the neurological symptoms. He also recalled a flu-like syndrome starting 55 days before GBS onset. The latter was characterized by low-grade fever and diarrhea for 7 days. Despite the fact that the patient never experienced respiratory symptoms, chest computed tomography (CT) scan revealed the presence of bilateral ground-glass opacities. Nasopharyngeal swab was negative for SARS-CoV-2 in two independent tests performed on real-time reverse transcriptase–polymerase chain reaction (RT-PCR) assay. The presence of SARS-CoV-2 was subsequently excluded also in the gastric aspirate and in the sputum. Additionally, PCR for influenza A and B viruses and serology for Borrelia and tick-borne encephalitis (TBE) resulted negative. CSF analysis revealed albumin-cytologic dissociation (increased protein content [193 mg/dL] and normal white cell count), while nerve conduction studies were compatible with a demyelinating process (Table 1). A brain magnetic resonance imaging (MRI) excluded an involvement of the central nervous system. The patient was treated with intravenous immunoglobulin with gradual clinical improvement. At last follow-up, 25 days after onset, only mild difficulty in tandem gait and diffuse hyporeflexia persisted.

Table 1 Clinical course and paraclinical studies
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Immunological investigations

The presence of antibodies for SARS-CoV-2 was investigated using 3 different techniques in both serum and cerebrospinal fluid (CSF): (1) rapid serological test (Cellex, USA); (2) enzyme-linked immunosorbent assay—ELISA (Eurospital Diagnostic, Italy); (3) paramagnetic particle chemiluminescent immunoassay—CLIA (YHLO, China).

Serum resulted IgG and IgM highly positive showing specific reactivity against SARS-CoV-2 nucleocapsid and spike 1 and 2 glycoproteins. CSF resulted strongly positive for IgG and IgM by rapid test and IgG positive with specific reactivity against nucleocapsid and spike 2 glycoprotein by ELISA.

A large panel of autoantibodies was also tested in serum, revealing negative anti-ganglioside IgG and IgM antibodies (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b), low-positive ANA (1:80, fine-speckled pattern), low-positive anti-SSA Ro52 and Ro60 antibodies, positive p-ANCA (1:160) with negative anti-myeloperoxidase and proteinase 3 antibodies, and negative anti-dsDNA antibodies. Cryoglobulins and HCV antibodies resulted also negative, while C3 and C4 complement components were within normal range.

Human leukocyte antigen (HLA) was analyzed, showing the following genotype: A*02:01,*33:01; B*14:02,*51:01; C*07:01,*08:02; DRB1*01:02,*03:01; DQA1*01:XX,*05:01; DQB1*02:01,*05:01.

Cytokines were measured in serum and CSF by multiplex ELISA assay (Bio-Techne, USA), demonstrating moderate increased levels of serum IL-6 (49 pg/mL), IL-8 (26 pg/mL), and TNF-α (16 pg/mL). In CSF, only IL-8 showed a significant increase (121 pg/mL) (Table 2).

Table 2 Serum and CSF levels of cytokines
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Discussion

We report herein the clinical and immunological findings in a case of Si-GBS, suggesting that (1) GBS can develop even after paucisymptomatic COVID-19 infection; (2) a distinctive cytokine repertoire is associated with this complication, with increased CSF concentration of IL-8; and (3) a particular genetic predisposition can be relevant in this setting; therefore, we provided the associated HLA of the patient, paving the way for future studies exploring his role in COVID-19-associated-GBS.

On a clinical standpoint, it is possible that the patient was either infected 2 months before GBS with a mild clinical infection (a much longer delay than expected) [5] or, more likely, that he developed an asymptomatic infection approximately 2 weeks before GBS. The possibility of asymptomatic COVID-19 infection [6], along with infection spreading and positive chest CT for asymptomatic individuals [7], was previously demonstrated and raised the important clinical question on whether we should test for SARS-CoV-2-antibody patients with GBS without symptomatic preceding infection.

To the best of our knowledge, this is the first case of Si-GBS in which SARS-CoV-2 antibodies were detected in the CSF, further strengthening the role of the virus as a trigger. Moreover, despite the great focus on IL-6 pathway in COVID-19 [8], we observed a much greater increase of the CSF concentration of IL-8. This cytokine was found to be highly elevated in a case of steroid-responsive encephalitis induced by SARS-CoV-2 [3].

Even if it is not possible to establish firm conclusions on the role of HLA in Si-GBS based on the data of a single patient, it is interesting to note that the presented patient harbored several HLA alleles known to be associated with GBS. In particular, regarding class I alleles, HLA-A33 was previously associated with acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in China [9]. The class II allele DRB1*03:01 was also associated with GBS in Iraq [10], while DQB1*05:01 was linked with severe GBS in a study performed in Germany [11]. Further studies are needed to conclude on the relevance of these findings, but it is likely that HLA plays a role in this setting as in other autoimmune neurological syndromes [12], including those triggered by infections.

In conclusion, our study suggest that SARS-CoV-2 Abs need to be searched in the serum and CSF in patients with GBS living in endemic areas, even in the absence of a clinically severe COVID-19 infection, and that IL-8 pathway can be relevant in Si-GBS pathogenesis.