Guillain Barré syndrome associated with COVID-19- lessons learned about its pathogenesis during the first year of the pandemic, a systematic review.

Dear editor,

The disease caused by the coronavirus SARS-CoV-2 (COVID-19), which emerged in China in December 2019 [1], has become a global pandemic in just a few months. The concomitant presentation of COVID-19 and some autoimmune diseases has also been reported, among which is Guillain Barré Syndrome (GBS) [2]. GBS is considered an immune-mediated neuropathy preceded 1 to 6 weeks in 70% of cases by a bacterial or a viral infection. In many cases associated with Campylobacter jejuni (the predominant pathogen) the presence of antiganglioside antibodies is observed. This supports a post-infectious mechanism, with molecular mimicry and antibody cross-response [3]. However, in GBS associated with Zika virus infection, an earlier onset is seen, and associated antiganglioside antibodies are rarely present, suggesting a para-infectious pathogenetic mechanism [4]. There is contradictory information on whether GB associated with COVID-19 has also characteristics that may indicate a para-infectious pathogenetic process [[5], [6], [7]]. To review the accumulated evidence about the pathogenic mechanism of this association, we carried out a review of the literature with a selection of the clinical cases reported until February 1st 2021, adding one own case. We selected studies reporting adult patients with all: Guillain-Barré syndrome, according to diagnostic criteria of the GBS Classification Group [8]; SARS-CoV-2 infection confirmed by nasopharyngeal reverse transcription polymerase chain reaction, antigen-detecting rapid diagnostic tests or serum antibody test; Detailed individual clinical description; A minimum of 6/8 points using the Joanna Briggs Institute Critical Appraisal Checklist for Case Reports and for Case Series studies [,][106], [107]. Finally, we selected 82 full text access articles with information about 104 clinical cases (Table 1 ) to which we added our own case (Patient 32). We searched suggestive features of the three pathogenic pathways proposed to neurologic damage in COVID-19 so far [11,12]: direct damage, dysregulated inflammatory response and antibody-mediated injury (Fig. 1 ). Direct damage: As seen in some viral infections such as poliovirus, enterovirus D68, cytomegalovirus, or other human coronaviruses, SARS-Cov-2 has neuroinvasive capacity [12,13]. The proposed access routes have been through circulation, the blood-brain barrier, or retrograde axonal transport, through the olfactory nerve or the enteric nervous system [12]. Endothelium, glial cells, and neurons express angiotensin-converting enzyme receptor 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), both necessary for the virus to get into the cells [14]. A post mortem study found SARS-CoV-2 RNA in neuroanatomical areas receiving olfactory tract projections [15]. However, PCR in CSF for COVID -19 virus was negative in all reported cases of GBS (Table 1), suggesting no intrathecal viral replication. Furthermore, a recent systematic review and meta-analysis showed that no study detected live SARS-COV-2 in various body fluids beyond day 9 of illness [16] and yet the median days of infection until the debut of GBS in the actual review has been 11 days. Dysregulated inflammatory response: In the ”inflammatory phase” of COVID-19 infection, which characteristically begins throughout the second week of infection, elevated IL-2, IL-2R, IL-6, IL-10, IFN-γ, TNF-α, CCL2, procalcitonin, CRP, erythrocyte sedimentation rate and white blood cell, are characteristic [17]. In 2005, brain autopsy studies demonstrate the infiltration of monocytes, macrophages, and T-lymphocytes into gliocytes and brain mesenchyme of SARS-CoV patients [19]. Pilotto et al. has also described the presence of elevated neuroinflammatory parameters (IL-6, IL-8, β2M and TNF-α) in the CSF of 13 patients with encephalitis and COVID-19 [20]. On the other hand, marked increase of cytokines has previously been reported in GBS and its variants, as well as in experimental autoimmune neuritis, the animal model of GBS [21]. Cell-mediated immunity seems to play a crucial role in immunopathology of all types of GBS, especially the AIDP subtype [22]. Of note, AIDP subtype is the predominant in the current systematic revision (73%, counting with mixed forms) (Table 1). Also, in the present work the medium time between the onset of COVID-19 and the neurological symptoms was 11 days, that is, in the stages of the infection in which inflammatory processes predominate over antibody-mediated. In addition, serum inflammatory parameters were elevated at the beginning of the neurological symptoms in 39/53 patients (73%). Antibody-mediated injury. Anti-GM1 IgG are present in a high proportion of patients with classic GBS, mostly those with AMAN or AMSAN. Also, anti-GQ1b IgG antibodies are present in in 80–95% of patients with Miller-Fisher syndrome (MFS), the most common clinical variant of GBS [23]. Nevertheless, Keddie et al. found no significant similarity between SARS CoV-2 and human genome [24] and only 6/58 cases (10%) in our review had positive antiganglioside antibodies, interestingly only 3 of the 17 patients with Miller-Fisher syndrome (20%) (Table 1). Patient number 92 was seropositive for IgM antibodies against panneurofascin without posterior seroconversion to IgG [25]. However, anti-neurofascin antibodies may also have been triggered by tissue damage related to GBS.

Table 1

Clinical cases obtained in the systematic review of the literature of patients with Guillen Barre Syndrome and a proven history of SARS-Cov-2 infection. Demographic and clinical characteristics, complementary examinations and evaluation of the quality of the case report.

First author (Ref.)		Age	Sex	Severity COVID19 1	Latency2	GBS Clinical variant3	EMG	SARS-COV-2 CSF	Antiganglioside antibodies	Biomarkers	Treatment COVID-19	Treatment GBS	Evolution at day 30	Study quality [[106], [107]]
Abbaslou [26]	Patient 1	55	F	3	32	paraparetic GBS	AMSAN	‐–	‐–	‐–	LPV/r	Ig iv	dead (ARDS)	7/8
Abolmaali [27]	Patient 2	88	F	3	‐−3	classic SGB	AMSAN	‐–	‐–	‐–	DEXA, LPV/r, HCQ	PPH	poor	7/8
	Patient 3	58	M	4	9	classic SGB	AMSAN	‐–	‐–	‐–	Remdensivir, Favipiravir, LPV/r, HCQ	Ig iv + PPH	dead (multi-organ failure)	7/8
Abrams [28]	Patient 4	67	F	2	10	classic SGB	‐–	PCR Neg	Neg	elevated DD, CRP, IgM	‐–	PPH	partial improvement	7/8
Agosti [29]	Patient 5	68	M	2	5	classic SGB	AIDP	‐–	‐–	thrombocythaemia, lymphopenia	antiviral	Ig iv	partial improvement	7/8
Alberti [30]	Patient 6	71	M	2	4	classic SGB	AIDP	PCR Neg	‐–	‐–	LPV/r, HCQ	Ig iv	dead (ARDS)	7/8
Ameer [31]	Patient 7	30	M	1	4	classic SGB	AMAN	PCR Neg	Neg	lymphopenia	‐–	Ig iv	complet recovery	8/8
Arnaud [32]	Patient 8	64	M	2	21	classic SGB	AIDP	PCR Neg	Neg	‐–	CXM, AZM, HCQ	Ig iv	complet recovery	8/8
Assini [33]	Patient 9	55	M	3	‐–	Miller-Fisher	AIDP	PCR Neg	Neg	lymphopenia, elevated ferritine, CRP, LDH, oligoclonal bands	HCQ, LPV/r Arbidol	Ig iv	complet recovery	7/8
	Patient 10	60	M	3	‐–	classic SGB	AMSAN	‐–	Neg	lymphopenia, elevated LDH y GGT, oligoclonal bands	HCQ, LPV/r, TCZ	Ig iv	partial improvement	6/8
Atakla [34]	Patient 11	40	M	3	11	classic SGB	AIDP	PCR Neg	‐–	neutropenia, elevated ESR, CRP	AZM	Ig iv	partial improvement	7/8
Barranchina-Esteve [35]	Patient 12	54	F	3	0	classic SGB	AMSAN	PCR Neg	Neg	elevated DD, ferritine, LDH	CXM, AZM, HCQ, LPV/r, MP, TCZ	Ig iv	complet recovery	8/8
Bigaut [36]	Patient 13	43	M	2	21	classic SGB	AIDP	PCR Neg	Neg	‐–	‐–	Ig iv	partial improvement	8/8
	Patient 14	70	F	3	7	classic SGB	AIDP	PCR Neg	Neg	elevated CRP	‐–	Ig iv	partial improvement	8/8
Boostani [37]	Patient 15	37	M	3	15	classic SGB	AIDP	‐–	‐–	elevated ESR, CRP	‐–	Ig iv	partial improvement	7/8
Bracaglia [38]	Patient 16	66	F	1	‐–	classic SGB	AIDP	‐–	Neg	lymphopenia, elevated CRP, CK, LDH, TGO, TGP, IL-6	LPV/r, HCQ,	Ig iv	partial improvement	7/8
Bueso [39]	Patient 17	60	F	2	22	classic SGB	‐–	‐–	‐–	‐–	AZM, HCQ	Ig iv	partial improvement	7/8
Caamaño [40]	Patient 18	61	M	2	10	BWDP	‐–	PCR Neg	‐–	‐–	HCQ, LPV/r	PRED low dose	partial improvement	8/8
Camdessanche [41]	Patient 19	64	M	2	11	classic SGB	AIDP	‐–	Neg	‐–	LPV/r	Ig iv	‐–	6/8
Chan [42]	Patient 20	58	M	2	‐–	BWDP	AIDP	PCR Neg	‐–	thrombocythaemia, elevated DD	CXM, AZM,	Ig iv	partial improvement	7/8
Civardi [43]	Patient 21	72	F	1	10	classic SGB	AIDP	PCR Neg	anti-GM1, anti-GD1a and anti-GD1b	elevated fibrinogen, CRP	HCQ, DOX,	Ig iv	partial improvement	8/8
Coen [44]	Patient 22	70	M	1	10	classic SGB	AIDP	PCR Neg	Neg	‐–	‐–	Ig iv	partial improvement	8/8
Colonna [45]	Patient 23	62	M	3	21	classic SGB	AIDP	‐–	‐–	elevated CRP	LPV/r, MP (60 mg/24 h)	Ig iv	partial improvement	7/8
Defabio [46]	Patient 24	70	F	1	90	classic SGB	‐–	‐–	‐–	ND	ND	Ig iv	complet recovery	7/8
Diez-Porras [47]	Patient 25	54	M	1	5	classic SGB	AIDP	‐–	IgM for GM2 and GD3 and a weak IgG for GT1b	elevated CRP, LDH y CK	AZM, HCQ, LPV/r	Ig iv	partial improvement	7/8
El Otmani [48]	Patient 26	70	F	2	3	classic SGB	AMSAN	PCR Neg	‐–	lymphopenia	HCQ, AZM	Ig iv	poor	7/8
Elkhouly [49]	Patient 27	75	M	‐–	‐–	classic SGB	‐–	‐–	‐–	‐–	MP	Ig iv	partial improvement	6/8
Esteban [50]	Patient 28	55	F	2	14	classic SGB	AIDP	‐–	‐–	elevated CRP	HCQ, CXM, AZM	Ig iv	partial improvement	7/8
Farzi [51]	Patient 29	41	M	2	10	classic SGB	AIDP	‐–	‐–	lymphopenia, elevated CRP	LPV/r, HCQ	Ig iv	partial improvement	7/8
Fernandez-Dominguez [52]	Patient 30	74	F	2	15	Miller-Fisher	AIDP	‐–	Neg	‐–	HCQ, LPV/r	Ig iv	partial improvement	7/8
Ferraris [53]	Patient 31	65	F	4	23	classic SGB	AIDP	‐–	‐–	elevated IL-6	HCQ, HBPM, AZM, TCZ, LPV/r, MP	Ig iv	partial improvement	7/8
Freire	Patient 32	71	M	2	9	classic SGB	AIDP	‐–	Neg	Elevated CRP, DD, LDH, ferritin, IL-6	MP	Ig iv	partial improvement	7/8
Gale [54]	Patient 33	58	M	2	‐–	classic SGB	AIDP	‐–	‐–	lymphopenia, elevated CRP	‐–	Ig iv	partial improvement	6/8
Garcia-Manzanedo [55]	Patient 34	77	M	2	21	PCBW	Mixed	‐–	‐–	‐–	LPV/r, HCQ	Ig iv	partial improvement	7/8
Garnero [56]	Patient 35	65	M	2	‐–	classic SGB	AIDP	‐–	Neg	‐–	‐–	Ig iv	‐–	6/8
	Patient 36	73	M	2	0	classic SGB	‐–	PCR Neg	Neg	‐–	‐–	Ig iv	‐–	7/8
	Patient 37	55	M	2	20	Miller-Fisher-GBS overlap	‐–	PCR Neg	Neg	‐–	‐–	Ig iv	‐–	7/8
	Patient 38	46	F	1	3	classic SGB	‐–	PCR Neg	Neg	‐–	‐–	Ig iv	‐–	7/8
	Patient 39	60	M	2	20	classic SGB	AMSAN	PCR Neg	Neg	‐–	‐–	Ig iv	‐–	7/8
	Patient 40	63	F	2	15	classic SGB	AMSAN		Neg	‐–	‐–	Ig iv	‐–	7/8
Ghosh [57]	Patient 41	20	M	1	8	classic SGB	AMAN	‐–	Neg	lymphopenia	‐–	Ig iv	partial improvement	7/8

-: information not available; 1 1: uncomplicated disease, 2: mild pneumonia, 3: respiratory distress, 4: septic shock; 2 Days from onset of COVID-19 symptoms to onset of GB symptoms; 3 According to diagnostic criteria for GBS, MFS and their subtypes of the GBS Classification Group [8].; 4 JBI (Joanna Briggs Institute) Critical Appraisal Checklist for Case Reports and for Case Series studies [,]; F: female; M: male; BWDP: bifacial weaknees whit distal parestesias; PCBW: pharyngeal-cervical-brachial weakness; AMSAN: acute motor-sensory axonal neuropathy; AIDP: Acute inflammatory demyelinating polyneuropathy; AMAN: acute motor axonal neuropathy; Neg: negative; Pos: positive; PCR SARS-COV-2 CSF: Polymerase chain reaction detection of SARS-Cov-2 in cerebrospinal fluid; DD: D-dimer; CRP: c-reactive protein; ESR: erythrocyte sedimentation rate; LPV/r: Lopinavir/ritonavir; NE: not specified; HCQ: Hydroxychloroquine; CXM: ceftriaxone; AZM: azithromycin; MP: methylprednisolone; TCZ: tocilizumab; DOX: doxycycline; DXM: dexamethasone; Ig iv: intravenous immunoglobulins; PPH: plasmapheresis; PRED: prednisone; ARDS: acute respiratory distress syndrome.

Fig. 1

Existing hypotheses about pathogenic pathways for neurologic damage associated with COVID-19. A. Direct damage. SARS-COV-2 could reach the central nervous system through circulation or retrograde axonal transport, through the olfactory nerve or the enteric nervous system. B. Dysregulated inflammatory response. IL-2, IL-2R, IL-6, IL-10, IFN-γ and TNF-α, are elevated in the”inflammatory phase” of COVID-19 infection. These molecules can stimulate macrophages, dendritic cells, Schwann cells, and epithelial cells that would damage the nervous system. ACE2: Angiotensin-converting enzyme 2; TMPRSS2: Transmembrane protease, serine 2. C. Autoantibody-mediated injury. The existence of a cross-reactivity between epitopes of the SARS-CoV-2 spike and the glycolipids of the peripheral nerve would be probable. This figure was created using BioRender (https://biorender.com/).

In conclusion, the absence of autoantibodies in most GBS cases associated with SARS-CoV2 infection, would force us to think about pathogenic mechanisms other than molecular mimicry. Both the short of the interval of days between the onset of COVID-19 and the neurological symptoms, and the high proportion of patients with serum elevation of inflammation markers at the beginning of neurological symptoms, support the hypothesis that cell-mediated immunity could play a role, as previously proposed for GBS related to Zika.

Funding

The study had no specific funding.

Declaration of Competing Interest

The authors declare that no conflict of interest exists.