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Patients' attitude towards vaccination after Guillain Barré syndrome

Abstract Background and Aims Guillain Barré syndrome (GBS) could be triggered by an infectious disease but by vaccination as well. Thus, suffering GBS may influence patients' attitudes towards vaccination. Methods An anonymous questionnaire consisting of the Overall Neuropathy Limitations Score (ONLS), the short form‐36 health survey (SF‐36), and questions addressing patients' attitude towards vaccination was sent to members of a German GBS support group and to patients with GBS diagnosis who were treated at Jena University Hospital. Results Ninety‐seven questionnaires clearly stated GBS as a diagnosis and were included in the analysis. Although 19.6% of the GBS patients reported having no disability in the long‐time follow‐up, a considerable number of patients still had persistent neurological symptoms; 74.2% of the GBS patients reported being able to walk at least 10 m independently. However, 5.2% were restricted to wheelchair. The patients reached lower scores in all domains of quality of life compared to German controls. Moreover, patients showed a more critical attitude towards vaccination compared to a German representative survey. Fewer patients (58.8%) received a vaccination after suffering from GBS than before (77.3%). Every tenth patient believed that vaccination was the trigger for the GBS. 32% of the patients did not receive a vaccination in the last 5 years mainly because of the fear of adverse effects (32%) or disadvise of the general practitioners (25.8%). Discussion Although the risk of relapse following immunization may be rather low, uncertainties and fears still impair the counseling of these patients by their medical practitioner.

immunoglobulin are proven effective treatments for GBS. 5 About 25% of patients develop respiratory insufficiency, 6 and many show signs of autonomic dysfunction 7 that mainly demands intensive care treatment. GBS is typically triggered by an infectious disease and may be associated with various pathogens (eg, campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, mycoplasma pneumonia, haemophilus influenzae, influenza A virus, and others). In addition, GBS was also found in patients with COVID-19, [8][9][10][11] but also influenza vaccination, trauma, surgical intervention, and others may be a potential trigger to develop GBS.
Functional outcome is associated with the amount of axonal damage. [12][13][14] Incomplete recovery is mainly caused by residual neuropathy affecting various parts of the peripheral nervous system after the acute phase of GBS, 15 and therefore, may cause significant impairment of quality of life. 16 However, functional recovery may be heterogeneous due to heterogeneity in pathophysiology, severity, duration of the disease, beginning of treatment, and individual comorbidities of the patients.
In addition, GBS has been generally considered to be a vaccine-associated adverse event 17 18 In addition, a meta-analysis 19 based on six adverse event monitoring systems with about 23 million vaccinated people showed that Influenza A (H1N1) 2009 vaccines were associated with a small increased risk of GBS.
However, at the end of the 2009 pandemic, the cumulative GBS risk was less among the pH1N1vaccinated than the unvaccinated population, rather suggesting a benefit of vaccination as it relates to GBS. 20 Nevertheless, patients may fear potential recurrences of GBS following vaccination, 21 which, in turn, may influence patients' behavior and attitude relating to vaccination and introduce uncertainties in the counseling of these patients by the general practitioner. This becomes increasingly relevant in the focus of actual COVID-19 vaccination programs, although COVID vaccination was not available at the timepoint of this survey. Here, we performed a survey focusing on the attitude towards vaccination of patients after suffering from GBS.

| METHODS
An anonymous questionnaire was designed, which included the following subsets: General information of the patients were collected (age, gender, year of the disease onset, diagnosis).
Questions relating to the attitude towards vaccination were partly taken from a German representative survey of prevention of infection, 22 which is an opinion survey of 5054 interviewees to attitude, knowledge, and behavior regarding vaccination. In addition, some GBS-specific questions were designed to evaluate a possible influence of the GBS towards the attitude concerning vaccination. The questions used in the questionnaire are collected in Table 1.
For evaluating the disability of the patients due to neuropathic symptoms, the ONLS (Overall Neuropathy Limitations Score) was used. 23 The ONLS is a scale that measures limitations in the everyday activities of the upper and lower limbs, and therefore, focuses on daily relevant activities. It is validated as an observed measure by clinicians watching patients perform the tasks. 23 In this study, the patients were asked to evaluate their abilities by themselves or by their relatives. Quality of life was evaluated using the short form-36 health survey (SF-36). 24,25 The SF-36 is a validated patient-reported survey of patient health and comprises eight domains (physical functioning, role physical, bodily pain, general health perception, vitality, social functioning, role emotional, mental health). All statistical analyses were performed using SPSS 27.0 (SPSS Inc., Chicago, IL, USA). Differences in self-reported features between groups were calculated using the t-test with a two-sided significance level of P < .05%.
Missing values in the SF-36 questionnaire were substituted with person-specific estimates if the respondent answered at least 50% of the items in a domain according to the half-scale rule from the SF-36 developers. 26 The raw data of the SF-36 were transformed to z-scores based on a German normative sample. 24 A zscore describes the position of a raw score in terms of its distance from the mean when measured in SD units. The z-score is positive if the value lies above the mean and negative if it lies below the mean.

| RESULTS
Totally 130 patients filled out and returned the questionnaires, but only in 97 questionnaires, GBS was clearly stated as a diagnosis and could finally be included in the analysis. CIDP was stated in 26 cases as diagnosis, and 7 did not state a diagnosis at all so that these questionnaires were excluded from the analysis. The basic characteristics of the patients can be seen in Table 2.

| Attitude towards vaccination
Totally 77.3% (n = 75) received a vaccination before suffering from GBS, but only 58.8% (n = 57) were vaccinated after GBS. 11.3% (n = 11) believe that a vaccination has triggered the GBS and 38.1% (n = 37) reported to be anxious that a vaccination may trigger a recurrence of the GBS.
Compared to the results of the German representative study, 22 where 5054 people were interviewed for attitude, knowledge, and behavior with regard to vaccination, the GBS patients of our study showed a more critical attitude towards vaccination ( Figure 1); 25% of the GBS patients reported being deprecatory or rather deprecatory against vaccination. Comparing the patients from the self-help group with the former hospital patients showed a significant difference (Chi-square test, P = .043) implying that the patients from the self-help group showed the most critical attitude against vaccination (34% vs 15% deprecatory or rather deprecatory). Further results are shown in Figure 2.
Of the GBS patients, 36.1% (n = 35) reported having taken advice regarding vaccination in the last 2 years; 68% have been vaccinated in the last 5 years, in most cases, against tetanus or seasonal flu. There was no correlation with age (Table 3). Regional differences were not collected and could not be analyzed. Table 3 gives an overview of the  12.5% reported a total score larger than 5 with rather significant disability.

| Disability and quality of life
All patients scored lower in all items of the SF-36 when compared with the normal German population. 24 No statistically significant differences (t-test) in the SF-36 scores were detected between patients from the support group and the former patients of the university hospital. Figure 3B shows the results of the SF-36 survey. The ONLS score showed the highest Pearson correlation coefficients to physical functioning (À0.689, P < .001) and role physical (À0.595, P < .001).

| Correlations
The semiquantitative scores for the attitude towards vaccination were weakly correlated to the ONLS score (Pearson correlation 0.219,

F I G U R E 1 Attitude towards vaccination in the GBS patient group and in the German representative survey 22
F I G U R E 2 Additional questions regarding patients' attitude towards vaccination P = .33, Figure 4), while no significance was found for a correlation to age or the SF-36 scores. In contrast, large epidemiological studies have shown that GBS rates after the influenza vaccine have been less than one case per million vaccinated people. 27 In addition, influenza vaccine-induced relapse of GBS also is evaluated as to be extremely seldom, so that prior GBS should not preclude influenza vaccination. 28 Even the risk of developing a GBS relapse is very low after mRNA COVID-19 vaccine application. 29 Thus, it can be concluded that also post-GBS patients can be vaccinated safely. It has been stated that the risk of GBS is 4-7 times higher after influenza infection than after influenza vaccine. 32 Less than 1 case of GBS per million immunized persons might occur for these vaccines. 33 Weighing up the hypothesized risks of adverse events, such as GBS, and the beneficial effects of vaccination, it can be argued that the potential risk to develop GBS cannot be considered a valid reason to avoid the administration of currently recommended vaccines. 33 A major concern is that vaccination may trigger a relapse of GBS.

| DISCUSSION
Recently, a large population-based nested case-control study found no evidence that demonstrated an association of vaccines with an increased risk of GBS and its recurrence within the 180 days following Our study was partly based on questionnaires sent to patients who are members of a patient organization, which makes this study susceptible to recall and selection bias. However, no statistically significant differences have been found (t-test) between patients contacted via patient organization (n = 71) and patients who were treated at Jena University Hospital (n = 48) neither in ONLS scores nor in SF-36 scores. However, the patients from the self-help group showed a more critical attitude towards vaccinations compared to the former hospital patients.
The questionnaires were sent to more than 800 persons, but less than 100 could be included in this study. This has led to a selection bias towards possibly more severe cases with unfavorable outcomes as the reported outcomes were more severe than in many of the population-based outcome studies cited above. Thus, it has to be kept in mind that the data represent the attitude in a very selective group of patients.

FUNDING
No funding.

CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. Hubertus Axer has full access to all the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

TRANSPARENCY STATEMENT
We confirm that this manuscript is an honest, accurate, and transparent account of the study being reported, no important aspects of the study have been omitted, and all discrepancies from the study as planned have been explained.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request. ORCID