Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and has caused a pandemic of Coronavirus Disease 2019 (COVID-19) [1]. Several immune-mediated neurological disorders after COVID-19 infection have been reported, including Guillain-Barré syndrome (GBS) [2].

GBS is an important cause of acute flaccid paralysis and is characterized by symmetrical weakness of the limbs, with or without cranial and sensory nerve deficits, and hyporeflexia or areflexia [3]. The subtypes of GBS include acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), Miller Fisher syndrome (MFS), pharyngeal-cervical-brachial weakness (PCB), acute motor sensory axonal neuropathy (AMSAN) and paraparesis [4]. GBS typically occurs after an infectious disease in which an aberrant immune response damage peripheral nerves [4]. Molecular mimicry is proposed as a leading mechanism for the potential link between certain infections and the onset of GBS, where the immune response to pathogens could mistakenly target neural tissues due to similarities in protein structures [5]. Pathogens causing antecedent infections related to GBS contains Campylobacter Jejuni, cytomegalovirus, Zika virus, Epstein-Barr virus, Mycoplasma pneumonia, Haemophilus influenzae, Japanese encephalitis virus, influenza A virus, chikungunya virus, and dengue virus [4,5,6].

An association between COVID-19 and the subsequent development of GBS has been observed, with an increasing number of cases reported globally [7]. SARS-CoV-2 may trigger GBS through molecular mimicry, aligning with known infectious precipitants [8]. Most previous studies attempted to investigate the relationship between COVID-19 and GBS by comparing the incidence of GBS before and during the pandemic [9,10,11]. However, the findings were inconsistent probably owning to varying degrees of the lockdown policy [10, 11]. The association between COVID-19 and GBS should be explored in the absence of COVID-19-mandated social restrictions.

The sudden change of public health policy regarding COVID-19 in China around December 7, 2022 caused an immediate large-scale outbreak of infections across the entire country lasting for approximately 2 months. It was estimated that 80% people were infected in this major outbreak [12]. The period gave a good opportunity to figure out the relationship between COVID-19 and GBS. This study aimed to compare the relative frequencies of GBS during the major outbreak at the end of 2022 and before COVID-19 pandemic, and investigate the distinctive clinical characteristics and prognosis of GBS associated with COVID-19.

Methods

Study design and participants

The present study was a retrospective, observational, single-center study investigating the potential relationship between COVID-19 and GBS. The major outbreak began from December 7, 2022 and subsided around January 20, 2023 (Fig. 1a-b). All of the GBS patients admitted to the First Hospital, Shanxi Medical University, from December 7, 2022 to February 20, 2023, and from June, 2017 to August, 2019 were included. The diagnosis of GBS was established using a previous criterion [13]. The relative frequencies of GBS before (from June, 2017 to August, 2019) and during the major outbreak (from December 7, 2022 to February 20, 2023) were compared. As cold season GBS peak has been reported [14], we also calculated the relative frequencies of GBS before and during the major outbreak within the same period across different years.

Fig. 1
figure 1

The daily number of reported Coronavirus Disease 2019 (COVID-19) cases and positive rate of COVID-19 testing in Chinese mainland (a-b) and the weekly number of COVID-Guillain-Barré syndrome (GBS) cases in our hospital (c) during the COVID-19 pandemic at the end of 2022. The COVID-19 was diagnosed based on SARS-Cov-2 RNA detection (a) or SARS-CoV-2 antigen (b)

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The patients with and without SARS-CoV-2 infection within six weeks prior to GBS onset formed the COVID-GBS group and non-COVID-GBS group, respectively. Another 110 COVID-19 hospitalized patients without GBS during the major outbreak were randomly selected as COVID-non-GBS group. None of these 110 patients had clinical symptoms or a diagnosis of GBS during hospitalization.

Information was collected from medical records, including demographic characteristics, related pre-illness conditions, clinical symptoms and signs, severity, Medical Research Council (MRC)-sumscores at nadir and discharge [15], laboratory and electrophysiological data, and treatment. The prognosis of COVID-GBS was investigated by telephone interview within three months after onset with GBS disability scale [16]. The clinical characteristics were compared between COVID-GBS and non-COVID-GBS and between COVID-GBS and COVID-non-GBS.

The diagnosis of GBS was made by a consensus of two neurologists in the Department of Neurology at our center on the basis of clinical presentation, cerebrospinal fluid (CSF) analysis, and electrophysiological studies recorded during hospitalization. The diagnoses of AMAN and AIDP were confirmed using Hadden’s electrodiagnostic criteria [17]. AMSAN was diagnosed by an absence of demyelinating features, as in Hadden’s criteria, and reduction in sensory nerve action potential amplitude < 50% of the lower limit of normal in at least two nerves [18, 19]. The COVID-19 was diagnosed based on SARS-Cov-2 RNA detection by reverse transcriptase polymerase chain reaction (RT-PCR) or SARS-CoV-2 antigen. The severity of COVID-19 was classified into asymptomatic or mild, moderate, severe and critical types according to the China COVID-19 guideline [20].

Statistics

Continuous data were expressed as means ± standard deviation (SD) or medians (range), and discrete variables were expressed as absolute values and percentages. Relative frequencies of GBS in patients hospitalized were calculated and compared between different periods with Poisson test. Percentages were compared between groups using Fisher exact test. Student t-test or Mann-Whitney U test was used to compare continuous variables depending on the distribution types. Two-tailed P-values < 0.05 were considered statistically significant. Descriptive statistics and preliminary data processing were performed using SPSS version 25.0 (IBM Corp, Armonk, New York). Advanced analyses, including the Poisson test, were conducted with R statistical software (version 4.2.3, The R Foundation for Statistical Computing). GraphPad Prism version 9.0 was used for the graphical representation.

Results

Epidemiological dynamics of the outbreak

According to the report from Chinese Center for Disease Control and Prevention (CCDC) [21], the outbreak of COVID-19 at the end of 2022 occurred between December 2022 and January 2023 (Fig. 1a-b). In total, 13 cases of GBS were diagnosed around the period, all of which had suffered from COVID-19 within six weeks prior to GBS onset. The first case developed symptoms of GBS at December 21, 2022 on week 3 of the outbreak, while the peaks of the COVID-19 epidemic and GBS cases were reached on week 3 and 5, respectively (Fig. 1c).

The relative frequency of GBS among all patients hospitalized in our hospital between December 7, 2022 and February 20, 2023 was 13/14,408 (0.090%). There were 29 cases with GBS identified between June, 2017 and August, 2019 in our hospital, with a relative frequency of 29/160,669 (0.018%). The relative frequency of GBS during the major outbreak of COVID-19 was significantly higher than that before the COVID-19 epidemic (Poisson test, RR 5.00, 95%CI 2.39–9.92, P < 0.001, Table 1). To exclude the seasonal effect, the relative frequency of GBS between December 7, 2017 and February 20, 2018 was calculated (3/12,513, 0.024%), also revealing a higher frequency during the major outbreak (Poisson test, RR 3.76, 95%CI 1.03–20.59, P = 0.041).

Table 1 The demographic and clinical characteristics between COVID-GBS and non-COVID-GBS
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Clinical characteristics of COVID-GBS and non-COVID-GBS

The demographics and clinical characteristics of patients with COVID-GBS and non-COVID-GBS are shown in Table 1. The mean age of patients with COVID-GBS was 53.92 ± 18.24 years and most were male (12/13). The age and sex differences between the two groups were comparable (P > 0.05). AIDP was the chief subtype in patients with COVID-GBS (11/13), and AMAN was more prevalent in non-COVID-GBS (15/27, P = 0.003). Correspondingly, more non-COVID-GBS patients (11/29) reported preceding gastrointestinal symptoms than COVID-GBS patients (0/13, P = 0.009). The mean interval between onset of infective symptoms and GBS was longer in COVID-GBS (21.54 ± 11.56 days) than in non-COVID-GBS (5.76 ± 3.18 days, P < 0.001). All but one case with COVID-19 developed GBS while the symptoms of COVID-19 going away. Cranial nerve involvement was more common in COVID-GBS (10/13) than in non-COVID-GBS (11/29, P = 0.019). The intervals between GBS onset and nadir and MRC-sumscores at nadir were similar between the two groups (P > 0.05).

CSF albuminocytologic dissociation (cell count < 50 cell/µl with elevated CSF proteins) [22] was noted in more than two-thirds of patients in both groups (P = 0.0682). The protein levels in CSF were significantly higher in COVID-GBS than in non-COVID-GBS (P = 0.021). Antiganglioside antibodies were uncommonly detected (2/9) in COVID-GBS, but the difference between the two groups was not significant (P = 0.596).

Most patients in both groups were treated with intravenous immunoglobulin (IVIg). The lengths of hospital stays were similar between the two groups (P = 0.469), and the severity at nadir and discharge was comparable between the two groups as reflected by MRC-sumscores (P = 0.257). Most patients with COVID-GBS responded well to IVIg and they achieved a median GBS disability score of 2 (able to walk 10 m or more without assistance but unable to run) within 3 months from a median score of 4 at nadir.

Clinical characteristics of COVID-19 in patients with GBS and non-GBS

The clinical characteristics of patients with COVID-GBS and COVID-non-GBS are shown in Table 2. Compared with COVID-GBS group (51 [27–85]), COVID-non-GBS patients were older (73[14–94], P < 0.002). Patients with COVID-non-GBS had a more-balanced gender ratio with male accounting for 56.4% (P < 0.012). Patients in the COVID-non-GBS group (3 [1-26]) had longer durations of COVID-19 respiratory symptoms before admission than those in the COVID-GBS group (7 [0–30], P = 0.033). The lengths of hospital stays were similar between the two groups (P = 0.382). COVID-non-GBS patients had more severe symptoms of COVID-19 than COVID-GBS patients. More than two-thirds of COVID-GBS patients (9/13, 69.2%) were asymptomatic or mild types of COVID-19, while only 21.8% in COVID-non-GBS group fell into the corresponding types (9/13 vs. 24/110, P = 0.001).

Table 2 The demographic and clinical characteristics between COVID-GBS and COVID-non-GBS
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Discussion

In this study, we found that there was a sudden increase in the number of GBS patients during the peak pandemic months, indicating an association between COVID-19 and GBS. Previous studies investigated the relationship between COVID-19 and GBS mainly by comparing the incidence of GBS before and during the pandemic [9,10,11]. The majority of the studies resulted in negative outcomes [9,10,11]. In fact, other factors in addition to COVID-19 affected the incidence of GBS. Strict lockdown policy reduced the number of GBS patients [10, 11]. A low prevalence of COVID-19 might diminish its effect on GBS [10]. During the major outbreak in China starting from December 7, 2022, 80% people were infected in the absence of social restrictions. Under this background, the relative frequency of GBS in hospitalized patients in the same hospital during the major outbreak in China was 5-fold higher than that before the epidemic of COVID-19 in the present study, which provided additional evidence for that COVID-19 was associated with GBS. Case-control studies are commonly used to look at factors associated with diseases [23]. One case-control study conducted in Spain revealed that SARS-CoV-2 infection was associated with a 6.3-fold increase in the incidence of GBS [24]. Another nested case-control study also suggested that SARS-CoV-2 infection was associated with increased risk of GBS [25].

The preceding infections influence the subtypes of GBS. C. jejuni and Zika virus infections are strongly associated with AMAN [26]. Most patients with GBS after influenza virus infection are categorized into AIDP [27]. AMAN was the most prevalent type of GBS in China and in our region [28, 29]. However, during the major outbreak, nearly all of the cases (11/13) with GBS were classified as AIDP, which was consistent with previous studies [7, 30], providing phenotypic evidence of association between SARS-CoV-2 infection and GBS. Accordingly, COVID-GBS patients exhibited higher prevalence of cranial nerve involvement and CSF protein concentrations, similar to patients with AIDP [4, 31].

The symptoms of COVID-19 in most patients with COVID-GBS were mild in this study, different from previous case reports [7], which indicated that occurrence of GBS was independent of the severity of COVID-19. At the time of GBS onset, the symptoms of COVID-19 disappeared in most COVID-GBS patients, suggesting a course of immune-mediated disease rather than virus damaging directly.

Although COVID-19 increases the incidence of GBS, it is not known whether the immune response toward SARS-CoV-2 damage peripheral nerves. An alternative hypothesis is that there is a secondary infection due to immune suppression caused by COVID-19, which induces GBS [32, 33]. Zhu et al. revealed that 242 of 257 COVID-19 patients (94.2%) were co-infected with one or more respiratory pathogens, several of which could cause GBS, including Haemophilus influenzae, Epstein-Barr virus, influenza A virus, Mycoplasma pneumonia, and cytomegalovirus [34]. In the present study, the COVID-GBS patients had a significantly longer average interval (21.54 ± 11.6 days) between preceding infections and GBS than those with non-COVID-GBS (5.76 ± 3.18 days), which supported the hypothesis. A systemic review included 436 COVID-GBS patients also indicated a similar mean interval (19 days) [35]. On the contrary, for example, the median time between infectious to neurologic symptoms was 3, 5 and 6 days in GBS patients associated with C. jejuni, Japanese encephalitis virus, and Zika virus infection, respectively [36,37,38]. An epidemiological study conducted in Finland revealed a mean interval of 12.4 days [39]. It is reasonable to speculate that a secondary infection following COVID-19 causes GBS, and therefore the interval between SARS-CoV-2 infection and GBS gets longer. Further evidence was needed to elucidate the molecular mechanism why COVID-19 increases the incidence of GBS [40].

Limitations

There are several limitations to our study. First, the study has a small sample size, which increases the sampling error. Meanwhile, this retrospective pilot study may have omitted some key information, and the completeness of the original data cannot be assured due to the nature of data collection post-case identification. Second, we recruited patients from a single hospital and the precise number of COVID-19 patients in the region was not available, and thus the incidence of GBS in COVID-19 patients could only be approximatively calculated and compared. Third, while our study suggests a potential link between secondary infections and the development of COVID-GBS, we did not specifically test for the immunoreactivity of the most prevalent infections in our geographic region among the patients. This limitation means that our conclusions are based on clinical inference rather than direct immunological evidence, which could provide a more definitive causal relationship.

Conclusions

COVID-19 significantly increased the incidence of GBS. Most COVID-GBS patients fell into the category of AIDP, responded well to IVIg, and had a favorable prognosis. Further studies investigating the co-infected pathogens among COVID-GBS patients and focusing on the molecular mechanisms of the association between COVID-19 and GBS should be conducted.