SARS-CoV-2 vaccinations reduce the prevalence of post-COVID Guillain-Barre syndrome

Highlights • SARS-CoV-2 infections can be complicated by Guillain-Barre Syndrome (GBS).• The prevalence of SARS-CoV-2 associated GBS declined since the introduction of SARS-CoV-2 vaccines.• The outcome of SARS-CoV-2 associated GBS is worse among those with comorbidities compared to those without.


Introduction
Guillain-Barr e Syndrome (GBS) is an increasingly perceived complication of SARS-CoV-2 (COVID- 19) infections. 1 In the first half of 2020, only a few patients with SARS-CoV-2 associated GBS (post-COVID GBS (PCG)) were published. 1−9 In the second half of 2020 the number of published PCG patients increased significantly. Since December 2020 several brands of SARS-CoV-2 vaccinations have been launched. It is unknown whether the frequency of PCG has decreased since the introduction of these anti-SARS-CoV-2 vaccinations. Therefore, the present narrative, up-to-date review aimed to compare the number, demographics, clinical presentation, therapeutic management, and outcome of PCG in the 6 months before and after vaccine availability (July to December 2020 compared with January 2021 to June 2021) and to answer the question of whether SARS-CoV-2 vaccinations reduce the prevalence of PCG.

Results
By the end of June 2021, a total of 124 articles were found that met the inclusion criteria and described individual patients with PCG ( Fig. 1). The first patient with PCG was reported by Zhao et al. in May 2020. 10,11 By the end of June 2020, 33 patients with PCG were published (Table 1). From July to December 2020, 192 PCG patients were published (Table 2). From January 2021 to the end of June 2021, a further 75 PCG patients were published (Table 3). The 124 articles published from early January 2020 to late June 2021 reported 300 patients with PCG (Table 4). Relevant data on age, gender, onset before/after COVID-19, latency between COVID-19 and onset of PCG, the subtype of GBS, PCR result in the Cerebrospinal Fluid (CSF), therapy, and outcome are presented in Table 4. The ages of these patients, available from 295 patients, ranged from 7 to 94y. The sex was male in 201 cases and female in 92 cases. The onset of PCG, available from 243 cases, was identified in 233/3/7 patients after/along with/before the onset of COVID-19. The latency between the onset of COVID-19 and the onset of PCG ranged from −10 and 90 days. The GBS subtype, reported in 233 cases, was identified as Acute, Inflammatory, Demyelinating Polyneuropathy (AIDP) in 171 patients, as Acute, Motor Axonal Neuropathy (AMAN) in 24, as Acute, Motor and Sensory Axonal Neuropathy (AMSAN) in 16, as Miller-Fisher Syndrome (MFS) in 8 patients, as Polyor Mono-Neuritis Cranialis (PNC/MNC) in 3, and as Pharyngeal, Cervical, and Brachial (PCB) variant in 1 patient. Bickerstaff Encephalitis (BFE) was not reported in any case. SARS-CoV-2 was only detected in the CSF of a single patient. Therapy of PCG, available in 270 cases, included Intravenous Immunoglobulins (IVIG) in 241 patients, plasmapheresis in 28, steroids in 7, and no therapy in 8 cases. Artificial ventilation was required for 59 patients. The outcome, available from 222 cases, was rated as full recovery (n = 42), a partial recovery (n = 163), or death (n = 17). Comparing patients with and without comorbidities, the incidence of a fatal outcome was higher in those with comorbidities than in those without. Among those with comorbidities, 8 died and among those, without comorbidities, only 5 died. The comparison of the patients published in the second half of 2020 with the patients published in the first half of 2021 showed that the number of publications and thus the number of patients had fallen from 192 to 75 patients in the first half of 2021 (Table 4).

Discussion
The review shows that PCG can be a complication of COVID-19 and suggests that SARS-CoV-2 vaccinations reduce the prevalence of PCG. Whether the prevalence of PCG has really increased since the outbreak of the pandemic is still a matter of debate. Some studies report an increase in the prevalence, others a decrease. 12,13 There are also studies that report no change in GBS prevalence since the outbreak of the pandemic. 14 Because CSF is devoid of viral RNA in almost all cases and because cytokines are elevated in the CSF in PCG patients, 15 an abnormal immune response rather than an infectious cause is the most likely pathophysiology underlying the development of PCG. Because PCG recovery is incomplete at discharge in most cases, PCG has to be classified as a serious complication of COVID-19.
The surprising finding that the number of reported PCG patients was lower in the first half of 2021 compared to the second half of 2020 can be asserted by several explanations. First, scientists are no longer interested in the topic as evidence accumulates that PCG is an established        complication of COVID-19. The interest in publishing established facts is therefore understandably low. Second, editors are no longer interested in publishing case reports or case series for the same reason. Third, COVID-19 patients were more severely ill than before in the first half of 2021 and therefore died prematurely before they could develop GBS. However, there is no evidence to support this speculation. In most registries, mortality from COVID-19 did not increase with the occurrence of more virulent variants of the virus. Fourth, the prevalence of PCG is actually declining either due to improved strategies to treat COVID-19 or due to the effect of vaccination. Since COVID-19 treatment has not changed and has not become more causal and effective than months before, the former speculations are rather unlikely. So if the prevalence of PCG has really decreased, a positive effect of vaccinations is conceivable.
In general, SARS-CoV-2 vaccinations not only have advantages but are sometimes accompanied by side effects, such as GBS. 16 Whether the prevalence of GBS as a side effect of SARS-CoV-2 vaccinations is higher compared to other vaccinations or whether PSG resulted in an overall increase in GBS prevalence is a matter of controversy. In a recent population-based historical rate comparison study and self-controlled case series analysis, only 11 PSG cases were observed after the first Astra Zeneca Vaccination (AZV) dose and only 5 PSG cases after the second dose. 17 Fewer than 5 PCG cases were reported among those who received the BioNtech Pfizer Vaccine (BPV) and no PCG cases among those who received the Johnson & Johnson Vaccine (JJV). 17 In a recent analysis of the US Vaccine Adverse Reporting System (VAERS) fewer than 1 PCG case per 1000,000 vaccine doses were reported within 42 days of vaccination in a period from January 2021 to 14th June 2021. 18 In this study neurological side effects were observed more frequently after use of the JJV than after the use of the BPV or the Moderna vaccine. 18 In a recent systematic review and metaanalysis of 48 publications reporting 2110,441,600 participants, the pooled incidence of PCG was 3.09 per 1 million people within six weeks of vaccination, which corresponds to 2.47 cases per 100,000 person year. 19,20 The pooled incidence was higher as compared to patients who received the influenza vaccine. 19 Regarding the treatment of PCG, it is not at a variance of that applied in patients with non-SARS-CoV-2 associated GBS. However, it is currently unknown whether the therapy is just as effective as in non-SARS-CoV-2 associated GBS. Recently, an emerging new treatment strategy for GBS has been proposed that may affect the prevalence of PCG ("zipper strategy"). 17 The approach is based on the combination of IVIG alternating with PE. 17 The therapy is based on the idea that PE eliminates the autoantibodies and cytokines and administering IVIG immediately after PE neutralizes those antibodies that are newly formed or transited from tissue. The subsequent PE session eliminates the antibodies away. 17 This new approach can improve the outcome of PCG patients. Since PCG strongly influences the outcome of SARS-CoV-2 infections and since the outcome of PCG is worse among those with than without comorbidities, PCG needs to be recognized early and comorbidities sufficiently treated to improve the overall outcome of COVID-19 patients.

Limitations
A limitation of the study is that publication dates do not necessarily reflect the dates when patients were diagnosed and treated. A further limitation is the design. A prospective, multicentre design is more appropriate than a retrospective design to assess a putative vaccination effect. Among the 7 patients in whom GBS seemingly preceded the viral infection, symptoms of the infection were either not adequately acknowledged or the infection initially remained asymptomatic.

Future directions
Future studies should focus on the question if SARS-CoV-2 vaccinations really reduce the frequency of SARS-CoV-2 infection-associated complications. More generally, they should assess if vaccinations improve the outcome of COVID-19 and reduce the rate of long-COVID, the frequency, and duration of hospitalizations, including the Intensive Care Unit (ICU), and if they reduce mortality.

Conclusions
The present study enriches the current literature as it shows that the prevalence of PCG appears to have decreased since the introduction of SARS-CoV-2 vaccines. To assess if SARS-CoV-2 vaccinations really reduce the prevalence of PCG, prospective, multicentre studies are urgently needed. If such studies confirm the results of the index study, vaccinations should be advocated and encouraged provided they are safe for everyone.

Declarations
Ethics approval and consent to participate: not applicable Consent for publication: not applicable Availability of data and material: all data reported are available from the corresponding author Funding: none received

Conflicts of interest
The authors declare no conflicts of interest.