Pain adverse events, Bell’s palsy, and Guillain-Barré syndrome Following Vaccination

Abstract

Objective

Some individuals (vaccinees) experience pain related adverse events following vaccinations. The majority of these pain related vaccination reactogenicity adverse events resolve within days. Rare adverse events like Bell’s palsy and Guillain-Barré syndrome (GBS) have been associated with some vaccines. Herein, multiple working hypotheses are examined in the context of available characteristics of vaccinees and onset of these pain related adverse events post vaccination.

Methods

The Vaccine Adverse Event Reporting System (VAERS) database was datamined for pain associated vaccine adverse events data by vaccine, age, gender, dose, and onset post vaccination. Results for vaccines with the highest number of pain related adverse events were compared.

Results

For the pain related adverse events examined, the highest number of adverse events are reported within 1 day, roughly half this number the second day, and roughly a quarter this number by the third day. The day of onset for these pain related adverse events approximates a power of two decay pattern for the first three days. This same pattern is observed for all of the vaccines with the highest number of pain related adverse events. The consistency of these day of onset frequency patterns of examined adverse events following vaccinations for multiple unrelated vaccines enables the exclusion of specific vaccine components and excipients as specifically causative entities.

Conclusion

The observed onset occurrences of examined pain associated adverse events are consistent with likely etiology relationship with innate immune responses to vaccinations for multiple vaccines including SARS-CoV-2 COVID-19, influenza, and additional vaccines. Innate immune responses may be contributing to the initial etiology of Bell’s palsy and GBS post SARS-CoV-2 mRNA and adenoviral vaccinations.

Introduction

Vaccines are designed to protect vaccinees (vaccinated individuals) against viral and bacterial infectious disease.  Some vaccinees experience one or more adverse events post vaccination.  Vaccine reactogenicity refers to the subset of adverse events that occur soon after vaccination and are physical manifestations of the inflammatory response to vaccination[1].  Most reactogenicity adverse events resolve within days.  Other adverse events have persistent symptoms that may last weeks, months, or longer.  The etiology of these adverse events remains unknown. 

Pain is a common element in a subset of the adverse events reported post vaccination.  Some adverse events like “injection site pain” have obvious causal relationship with injection vaccinations.  Other rare adverse events like Bell’s palsy and Guillain-Barré syndrome (GBS) can occur with causality difficult to assess with frequencies close to background occurrence frequencies[2,3].  GBS has been associated with influenza[4] and COVID-19 vaccinations[5].  GBS has been reported following Moderna[6–10], Pfizer BioNTech BNT162b2[11–19], Oxford AstraZeneca ChAdOx1 day[15,20–34], Johnson & Johnson/Janssen Ad26.CoV2.S[10,35–39], Sinopharm[33,34], and Sputnik V[34,40] COVID-19 vaccines.  Many GBS patients are expected as sporadic cases and should not be considered causal[41].  For Pfizer BioNTech BNT162b2 mRNA vaccine, no increased incidence of GBS in a cohort of 3.9 million recipients was detected[42].  A review of GBS incidence in Vaccine Safety Datalink found an increased incidence following Ad.26.COV.2 but not BNT172b2 or mRNA-1273 vaccines[43].  An excess of GBS cases following AstraZeneca-Oxford ChAdOx1-S vaccination has also been identified[44].   An increased risk for GBS after first dose but not second dose of ChAdOx1 nCov-19 vaccination has been reported[45].  Warnings that rare GBS cases may link to J&J and AstraZeneca vaccines have been issued[46].  One etiology model for GBS following COVID-19 vaccination is autoimmune autoantibodies[5]; but, no serum anti-ganglioside antibodies were found in 15 of 17 patients tested[47].  Nearly all GBS patients after COVID-19 vaccinations also had facial weakness or paralysis[43].  

Bell’s palsy is a disease characterized by a rapid and unilateral onset of peripheral paresis (paralysis) of the seventh cranial nerve.  Bell’s palsy has been reported as an adverse event following immunization for influenza[48] and COVID-19 CoronaVac (Sinovac Biotech, Hong Kong)[49].  Bell’s palsy cases have also been reported following Moderna mRNA-1273[50–54], Pfizer/BioNTech BNT162b2[55–59], Johnson & Johnson/Janssen Ad26.CoV2.S[60,61] COVID-19 vaccinations.  Burrows et al.[62] report a patient with sequential contralateral facial nerve palsies following the first and second doses of Pfizer-BioNTech BNT162b2 COVID-19 vaccine.  Other studies do not detect an enrichment signal for Bell’s palsy or facial paralysis with COVID-19 vaccines[2,63].  Some cases of facial paralysis may be caused by reactivation of latent herpes simplex virus (HSV)[64] or varicella zoster virus (VSV) in a mechanism similar to Ramsey Hunt syndrome.  An increased risk for Bell’s palsy has been observed for concomitant administration of meningococcal conjugate vaccine with another vaccine[65].  A population based study reported 132 cases in 2.6 million vaccinees and 152 cases in 2.4 million vaccinees after first and second doses for BNT162b2 mRNA COVID-19 vaccine[66].  An excess of 1.112 Bell’s palsy reports per 100,000 people who received 2 doses of BNT162b2 has been estimated[67].  Significantly fewer adverse neurological events were reported following BNT162b2 or mRNA-1273 vaccination compared to Ad26.CoV2.S[68].

The Vaccine Adverse Event System (VAERS) database tracks reported adverse events following vaccinations for the United States.  Herein, VAERS is data mined for reports of pain associated adverse events.  Multiple working hypotheses[69] are evaluated for pain related adverse events following vaccination leveraging these VAERS data mining results.

Methods

The Vaccine Adverse Event Reporting System (VAERS) database (https://vaers.hhs.gov)[70] was datamined for pain associated vaccine adverse events data by vaccine name or vaccine type, age, gender, dose, and onset post vaccination.   The downloaded data includes all VAERS reports from 1990 until May 13, 2022.  A Ruby program named vaers_slice.rb[71] was used to tally selected reported vaccine adverse events by vaccine.  The vaers_slice.rb program takes as input a list of one or more symptoms and outputs a summary of to the yearly VAERS Symptoms, Vax, and Data files from 1990 to 2022.  The output from vaers_slice.rb consists of five reports: summaries by vaccine, summaries by age of onset of symptoms, summaries by day of onset of symptoms, and two summaries of additional symptoms reported (selected symptoms and all other symptoms).  The VAERS adverse events by vaccine name were extracted for Abdominal pain, Abdominal pain lower, Abdominal pain upper, Arthralgia (pain in joint), Asthenia (abnormal physical weakness or lack of energy), Axillary pain, Back pain, Bell's palsy, Bone pain, Breast pain, Chest pain, Dysphagia (difficulty or discomfort in swallowing), Ear pain, Eye pain, Facial pain, Facial paralysis, Facial paresis, Guillain-Barre syndrome, Hemiparesis, Hypoaesthesia (partial or total loss of sensation), Injection site pain, Lymph node pain, Lymphadenopathy (enlarged lymph nodes), Musculoskeletal chest pain, Musculoskeletal pain, Musculoskeletal stiffness, Myalgia (muscle pain), Neck pain, Neuralgia, Oropharyngeal pain (mouth and pharynx pain), Pain, Pain in extremity, Pain in jaw, Pain of skin, Paraesthesia (an abnormal sensation, typically tingling or pricking), Renal pain, Spinal pain, and Swelling face were extracted.  The VAERS adverse events by vaccine type were extracted for Bell’s palsy, Fatigue, Guillain-Barre syndrome, Headache, Miller Fisher syndrome, and Pyrexia.  Microsoft Excel was used create figures.

Results

The results include all reports of selected adverse events from 1990 until May 13, 2022.  These adverse events share a non-random pattern of onset; Figures 1 and 2 illustrate this onset pattern for 16 pain associated adverse events in VAERS.  This onset pattern is also present for GBS and Bell’s palsy (Figures 3 and 4).  These adverse events also exhibit excess reports of pain associated adverse events post vaccination for females compared to males for twenty vaccines (Figure 5).   Summarized data, from vaers_slice.rb, for each VAERS pain associated adverse event are included in the supplemental data tables for days 0 to 120 for each vaccine with associated adverse event.  Some vaccinees experience more than one adverse event; correlations of reports of multiple pain associated adverse events are summarized in Table 1 for the most frequently reported adverse events and Table S1 for selected pain associated adverse events with all adverse events.   Each vaers_slice.rb report in the Supplemental data includes correlations with all other reported adverse events; the top 35 for selected pain adverse events are illustrated in Supplemental Table S2.  

Both GBS and Bell’s palsy are rare adverse events reported post vaccination.  The three most commonly reported adverse events for many vaccines are headache, fatigue, and pyrexia (fever).  The proportion of GBS and Bell’s palsy reports are compared to these commonly reported adverse events as a comparison metric for unrelated vaccines.  Proportional enrichment by vaccine for GBS and Bell’s palsy are calculated for three reactogenicity adverse events (headache, fatigue, and pyrexia/fever) in Tables 2 and 3.

Discussion

For all of the pain associated adverse events examined, the highest reports are within 24 hours of vaccination (day 0).  For each pain associated adverse event, the number of reports for day 1 are roughly half that of day 0; likewise, the number of adverse events reported for day 2 are roughly half that of day 1 (Figures 1 and 2).  Females report pain associated adverse events between two and three fold more frequently than males (Figure 5).   Vaccinees sometimes report more than one pain associated adverse event (Table 1).  For adverse events like injection site pain, this is consistent with expectations.  Other adverse events reported by vaccinees are nausea, headache, pyrexia, fatigue, chills, and other.  The consistency of the frequency patterns of these adverse events following vaccinations for multiple unrelated vaccines enables the exclusion of specific vaccine components and excipients as specifically causative entities; however, these components and excipients are likely the key determinants of the reactogenicity level associated with each vaccine.  Possible working hypotheses of the causes of pain, paresis, or paralysis related adverse events following vaccination include innate immune responses, inflammation, latent virus reactivation, and autoimmune antibodies.   

Vaccinations are designed to stimulate immune humoral (e.g., antibody) immune responses.  Vaccines elicit immediate innate immune responses from vaccinees.  These innate immune responses include the release of inflammatory molecules including chemokines, cytokines, interleukins, lymphokines, and monokines from immune cells[72–75].  The blood-nerve barrier is not as tight as the blood-brain barrier; it is possible for T cells and macrophages to leak in at inflamed tissue[76].  Vaccination-induced autoimmune antibody responses would require either primary humoral immune response or memory humoral immune responses; these humoral immune responses would peak roughly 7 to 10 days post vaccination.  Hence, autoimmune antibody responses are unlikely associated with the majority of observed immediate onset reactogenicity adverse responses observed (Figures 1, 2, and supplemental data).  Miller Fisher syndrome has some presentation overlaps with GBS[77]; like other examined adverse events, immediate onset signals also occur for Miller Fisher syndrome adverse events in VAERS associated with COVID-19 and influenza vaccines (supplemental data table V_Miller_Fisher).   Reactivation of latent viruses has been observed post SARS-CoV-2 vaccinations[78,79]; clinical and molecular evidence of reactivation of latent viruses associated with the majority of the reported pain associated adverse events is currently lacking.  While reactivation of latent viruses has occurred post vaccinations, the onset timing of 7 to 21 days[78,79] is inconsistent with observed immediate onset of pain associated adverse events.  Consistent with the observed immediate onset of reported pain associated adverse events, innate immune response molecules are known to be associated with pain.  These innate immune responses include the release of inflammatory molecules, including histamine, interleukin 1β (IL-1β), interleukin 6 (IL-6), monocyte chemoattractant protein (MCP-1), prostaglandin E₂ (PGE₂), tumor necrosis factor (TNF; formerly TNFα), etc.; these innate immune cells include macrophages, granulocytes including mast cells, T helper cells, and other immune cells[72,73,80,81].  PGE₂ is a well-known lipid mediator that contributes to inflammatory, neuropathic, and visceral pain, see[81].  IL-1β, IL-6, and TNF are involved in the process of pathological pain[73].  Histamine is known to be algesic (cause pain) to peripheral nervous system[75].  Type I interferons have been proposed as a potential mechanism linking COVID-19 mRNA vaccines to Bell’s palsy[82].  

4.1 Guillain-Barré Syndrome (GBS)

VAERS reports for GBS illustrate a pattern of immediate onset timing associated with seven vaccines (Figure 3).  The onset for the majority of the GBS reports are within 24 hours (day 0), roughly ½ this the next day (day 1), and roughly ¼ this the second day (Figure 3 and supplemental data table: V_Guillain_Barre).  This onset pattern is too rapid for molecular mimicry, epitope sharing, and autoimmune antibodies to be causative prior to day 7.  Similar patterns shared by COVID-19, Influenza, Shingles Zoster, human papillomavirus, and Pneumococcal vaccines support innate immune responses as a major component of disease early etiology.  Three of the highest frequencies reactogenicity adverse events shared across the examined pain related adverse events are headache, fatigue, and pyrexia (fever).  Examining the frequencies of GBS in proportion to these reactogenicity adverse events illustrates that the frequency of GBS is highest for Influenza vaccines with a lower frequency for COVID-19 vaccines (Table 2).  The general consistency of occurrence frequencies across all of the examined unrelated vaccines in Table 2 further supports the hypothesis that reactogenicity responses to vaccination in general are coupled to the frequency of GBS following vaccinations.  Clinically, most GBS patients following COVID-19 vaccination showed typical demyelination neuropathy with albumin-cytological dissociation[83]; the timing suggests that demyelination neuropathy and albumin-cytological dissociation might be subsequent events in the disease etiology for patients with immediate onset adverse events.  The immediate onset pattern of GBS following vaccination is different from the observed pattern for Zoster vaccines[84]; their reported Zoster vaccine onset pattern is consistent with the development of autoimmune antibodies in contrast to the immediate onset Zoster vaccine records in VAERS (Figure 3).  Note that autoantibodies are detected for some GBS patients post COVID-19 vaccination[14,85]; onset of GBS for multiple patients is consistent with the development of autoantibodies[9,13–15,19,22–31].

In one report, nearly all GBS patients after COVID-19 vaccinations also had facial weakness or paralysis[86].  Another report included nine GBS patients with rare subtype known as Bilateral Facial Palsy with paresthesias (BFP) with five vaccinated with Sputnick V and four with ChAdOx1.  Of these nine patients, four tested positive with ganglioside antibody panel (2: anti-GM1, antig-GD1a, and anti-sulfatide)[40].

4.2 Bell’s palsy

The frequency of Bell’s palsy is highest for COVID-19 and lower for Zoster and Influenza vaccines (Table 3 and Figure 4).  The frequencies for non-COVID-19 vaccines is low for vaccines but with enrichment for day 0 onsets for a few vaccines (supplemental data V_Bells_palsy).  Onset of Bell’s palsy within 5 hours of BNT162b2 vaccination[55] and 12 hours after mRNA-1273 vaccination[51] together with VAERS day 0 onset reports can be leveraged to limit candidate etiology possibilities.  The association pattern for immediate onset is consistent with innate immune responses for very high reactogenicity vaccines (COVID-19 mRNA and adenovirus) or concomitant administration of vaccines.  The working hypothesis for live Zoster vaccines reactivating latent Herpes family viruses is also consistent with current models for Bell’s palsy[73].

4.3 Persistent pain models

Candidate models for persistent pain include autoimmune antibodies, nerve damage and/or demyelination, reactivated latent viruses, immune cells infiltration at blood-never barrier during inflammation (albumin-cytological dissociation seen in GBS), innate immune cells with feedback loops with nerve cells, mast cell and eosinophil paired couplets, and ongoing expression of vaccine protein[87] by innate immune cells.  Immediate onset adverse event lymphadenopathy (Figure 2) is consistent with ongoing expression of vaccine protein by innate immune cells.   Mast cells and eosinophils are known to form bidirectional interactions resulting in a hyperactivated state, reviewed[88].  Additional research is needed to resolve the pathogenesis model(s) of persistent pain adverse events following vaccinations.  Immediate onset of pain related adverse events might suggest that early interventions might lessen the severity of symptoms and possibly even decrease the frequencies of occurrences.  Cellular feedback loops are possible between nerve cells and mast cells driving neurogenic inflammation and nociceptive pain[89].  

4.4 Histamine

Pain related inflammatory molecules released by innate immune responses include histamine.  Histamine is known to be associated with peripheral nerve pain[75,90].  Elevated histamine levels are predicted as drivers of cardiac adverse events including myocarditis and pericarditis[71] and menstrual adverse events[91].  Ongoing vaccine expression in innate immune cells, lasting months[87], may drive localized release of inflammatory molecules including histamine.  

4.5 Exploratory treatment candidates

Dampening histamine responses from innate immune mast cells may reduce the population frequency and severity of some pain adverse events following vaccinations.  Antihistamine treatments exhibiting efficacy in treating COVID-19 patients may target possible granulocytes and mast cells associated with vaccine responses.   Candidate treatments for evaluation include high dose famotidine[92–95], cetirizine[96,97], and dexchlorpheniramine[96].  Oral treatment with diamine oxidase may also be beneficial.  Alternatively, if mast cell and eosinophil couplets are involved, targeting them with anti-IL-5 (mepolizumab)[98] may be beneficial.  Evaluation of these treatments and treatment combinations on vaccinees in case reports, case series, etc. can inform subsequent randomized controlled clinical trials for reducing vaccine pain adverse events.  

4.6 Summary

Data mining VAERS for pain associated adverse events illustrates likely etiology of innate immune responses driving pain related adverse events post vaccination including rare reports of Guillain-Barré syndrome and Bell’s palsy.  The consistency of the frequency patterns of examined adverse events following vaccinations for multiple unrelated vaccines enables the exclusion of specific vaccine components and excipients as specifically causative entities.  Identification of likely role of innate immune responses in the etiology of pain related adverse events post vaccination suggest possible candidate treatments for evaluation in clinical studies. Innate immune responses may be contributing to the initial etiology of rare cases of GBS and Bell’s palsy post SARS-CoV-2 mRNA and adenoviral vaccinations.

Declarations

Acknowledgements

The authors thank Nora Smith for useful discussions.

Conflict of Interest

All authors declare no conflict of interest.

Author Contribution

Not applicable (this is a single-author research article).

Consent statement/ethical approval

Not required.

Funding

None

Supplementary Data

Complementary Supplementary Data Files were provided summarizing the pain related adverse events summarized from VAERS (Pain1.xlsx, Pain2.xlsx, & VaccineSummaries.xlsx).

Abbreviations

COVID-19, Coronavirus Disease 2019

GBS, Guillain-Barré syndrome

IL-1β, Interleukin 1β

IL-6, Interleukin 6

MCP-1 , Monocyte Chemoattractant Protein

PGE₂, Prostaglandin E₂

SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2

TNF, Tumor Necrosis Factor

VAERS, Vaccine Adverse Event System

References

[1]        Hervé C, Laupèze B, Del Giudice G, Didierlaurent AM, Tavares Da Silva F. The how’s and what’s of vaccine reactogenicity. NPJ Vaccines 2019;4:39. https://doi.org/10.1038/s41541-019-0132-6.

[2]        Renoud L, Khouri C, Revol B, Lepelley M, Perez J, Roustit M, et al. Association of Facial Paralysis With mRNA COVID-19 Vaccines: A Disproportionality Analysis Using the World Health Organization Pharmacovigilance Database. JAMA Intern Med 2021;181:1243–5. https://doi.org/10.1001/jamainternmed.2021.2219.

[3]        Shemer A, Pras E, Einan-Lifshitz A, Dubinsky-Pertzov B, Hecht I. Association of COVID-19 Vaccination and Facial Nerve Palsy: A Case-Control Study. JAMA Otolaryngol Head Neck Surg 2021;147:739–43. https://doi.org/10.1001/jamaoto.2021.1259.

[4]        Galeotti F, Massari M, D’Alessandro R, Beghi E, Chiò A, Logroscino G, et al. Risk of Guillain-Barré syndrome after 2010-2011 influenza vaccination. Eur J Epidemiol 2013;28:433–44. https://doi.org/10.1007/s10654-013-9797-8.

[5]        Khan Z, Ahmad U, Ualiyeva D, Amissah OB, Khan A, Noor Z, et al. Guillain-Barre syndrome: An autoimmune disorder post-COVID-19 vaccination? Clin Immunol Communications 2022;2:1–5. https://doi.org/10.1016/j.clicom.2021.12.002.

[6]        Dalwadi V, Hancock D, Ballout AA, Geraci A. Axonal-Variant Guillian-Barre Syndrome Temporally Associated With mRNA-Based Moderna SARS-CoV-2 Vaccine. Cureus 2021;13:e18291. https://doi.org/10.7759/cureus.18291.

[7]        Bijoy George T, Kainat A, Pachika PS, Arnold J. Rare occurrence of Guillain-Barré syndrome after Moderna vaccine. BMJ Case Rep 2022;15:e249749. https://doi.org/10.1136/bcr-2022-249749.

[8]        Matarneh AS, Al-battah AH, Farooqui K, Ghamoodi M, Alhatou M. COVID-19 vaccine causing Guillain-Barre syndrome, a rare potential side effect. Clin Case Rep 2021;9:e04756. https://doi.org/10.1002/ccr3.4756.

[9]        Masuccio FG, Comi C, Solaro C. Guillain–Barrè syndrome following COVID-19 vaccine mRNA-1273: a case report. Acta Neurologica Belgica 2021. https://doi.org/10.1007/s13760-021-01838-4.

[10]      Sriwastava S, Shrestha AK, Khalid SH, Colantonio MA, Nwafor D, Srivastava S. Spectrum of Neuroimaging Findings in Post-COVID-19 Vaccination: A Case Series and Review of Literature. Neurol Int 2021;13. https://doi.org/10.3390/neurolint13040061.

[11]      Hughes DL, Brunn JA, Jacobs J, Todd PK, Askari FK, Fontana RJ. Guillain-Barré Syndrome After COVID-19 mRNA Vaccination in a Liver Transplantation Recipient With Favorable Treatment Response. Liver Transpl 2022;28:134–7. https://doi.org/10.1002/lt.26279.

[12]      Aomar-Millán IF, Martínez de Victoria-Carazo J, Peregrina-Rivas JA, Villegas-Rodríguez I. COVID-19, Guillain-Barré syndrome, and the vaccine. A dangerous combination. Rev Clín Esp (Engl Ed) 2021;221:555–7. https://doi.org/10.1016/j.rceng.2021.05.002.

[13]      Bouattour N, Hdiji O, Sakka S, Fakhfakh E, Moalla K, Daoud S, et al. Guillain-Barré syndrome following the first dose of Pfizer-BioNTech COVID-19 vaccine: case report and review of reported cases. Neurol Sci 2022;43:755–61. https://doi.org/10.1007/s10072-021-05733-x.

[14]      Fukushima T, Tomita M, Ikeda S, Hattori N. A case of sensory ataxic Guillain–Barré syndrome with immunoglobulin G anti-GM1 antibodies following the first dose of mRNA COVID-19 vaccine BNT162b2 (Pfizer). QJM 2022;115:25–7. https://doi.org/10.1093/qjmed/hcab296.

[15]      Kim JW, Kim YG, Park YC, Choi S, Lee S, Min HJ, et al. Guillain-Barre Syndrome After Two COVID-19 Vaccinations: Two Case Reports With Follow-up Electrodiagnostic Study. J Korean Med Sci 2022;37. https://doi.org/10.3346/jkms.2022.37.e58.

[16]      Kim Y, Zhu Z, Kochar P, Gavigan P, Kaur D, Kumar A. A Pediatric Case of Sensory Predominant Guillain-Barré Syndrome Following  COVID-19 Vaccination. Child Neurol Open 2022;9:2329048X221074549. https://doi.org/10.1177/2329048X221074549.

[17]      Yamada S, Yamada K, Nishida H. A Case of Sequential Development of Polymyalgia Rheumatica and Guillain-Barré Syndrome Following Administration of the Pfizer-BioNTech COVID-19 Vaccine. Intern Med 2022;advpub. https://doi.org/10.2169/internalmedicine.0319-22.

[18]      Trimboli M, Zoleo P, Arabia G, Gambardella A. Guillain-Barré syndrome following BNT162b2 COVID-19 vaccine. Neurol Sci 2021;42:4401–2. https://doi.org/10.1007/s10072-021-05523-5.

[19]      Malamud E, Otallah SI, Caress JB, Lapid DJ. Guillain-Barré Syndrome After COVID-19 Vaccination in an Adolescent. Pediatr Neurol 2022;126:9–10. https://doi.org/10.1016/j.pediatrneurol.2021.10.003.

[20]      Ogbebor O, Seth H, Min Z, Bhanot N. Guillain-Barré syndrome following the first dose of SARS-CoV-2 vaccine: A temporal occurrence, not a causal association. IDCases 2021;24:e01143. https://doi.org/10.1016/j.idcr.2021.e01143.

[21]      Min YG, Ju W, Ha Y-E, Ban J-J, Lee SA, Sung J-J, et al. Sensory Guillain-Barre syndrome following the ChAdOx1 nCov-19 vaccine: Report of two cases and review of literature. J Neuroimmunol 2021;359. https://doi.org/10.1016/j.jneuroim.2021.577691.

[22]      Biswas A, Pandey SK, Kumar D, Vardhan H. Post Coronavirus Disease‑2019 Vaccination Guillain‑Barré Syndrome. Indian J Public Health 2021;65:422–4. https://doi.org/10.4103/ijph.ijph_1716_21.

[23]      Aldeeb M, Okar L, Mahmud SS, Adeli GA. Could Guillain–Barré syndrome be triggered by COVID-19 vaccination? Clin Case Rep 2022;10:e05237. https://doi.org/10.1002/ccr3.5237.

[24]      Kanabar G, Wilkinson P. Guillain‐Barré syndrome presenting with facial diplegia following COVID‐19 vaccination in two patients. BMJ Case Rep 2021;14:e244527. https://doi.org/10.1136/bcr-2021-244527.

[25]      Introna A, Caputo F, Santoro C, Guerra T, Ucci M, Mezzapesa DM, et al. Guillain-Barré syndrome after AstraZeneca COVID-19-vaccination: A causal or casual association? Clin Neurol Neurosurg 2021;208:106887. https://doi.org/10.1016/j.clineuro.2021.106887.

[26]      McKean N, Chircop C. Guillain-Barré syndrome after COVID-19 vaccination. BMJ Case Rep 2021;14:e244125. https://doi.org/10.1136/bcr-2021-244125.

[27]      Kripalani Y, Lakkappan V, Parulekar L, Shaikh A, Singh R, Vyas P. A Rare Case of Guillain-Barré Syndrome following COVID-19 Vaccination. EJCRIM 2021;8. https://doi.org/10.12890/2021_002797.

[28]      Hasan T, Khan M, Khan F, Hamza G. Case of Guillain-Barré syndrome following COVID-19 vaccine. BMJ Case Rep 2021;14:e243629. https://doi.org/10.1136/bcr-2021-243629.

[29]      James J, Jose J, Gafoor VA, Smita B, Balaram N. Guillain-Barré syndrome following ChAdOx1 nCoV-19 COVID-19 vaccination: A case series. Neurol Clin Neurosci 2021;9:402–5. https://doi.org/10.1111/ncn3.12537.

[30]      da Silva GF, da Silva CF, Oliveira REN da N, Romancini F, Mendes RM, Locks A, et al. Guillain–Barré syndrome after coronavirus disease 2019 vaccine: A temporal association. Clin Exp Neuroimmunol 2022;13:92–4. https://doi.org/10.1111/cen3.12678.

[31]      Patel SU, Khurram R, Lakhani A, Quirk B. Guillain-Barre syndrome following the first dose of the chimpanzee adenovirus-vectored COVID-19 vaccine, ChAdOx1. BMJ Case Rep 2021;14:e242956. https://doi.org/10.1136/bcr-2021-242956.

[32]      Allen CM, Ramsamy S, Tarr AW, Tighe PJ, Irving WL, Tanasescu R, et al. Guillain–Barré Syndrome Variant Occurring after SARS-CoV-2 Vaccination. Ann Neurol 2021;90:315–8. https://doi.org/10.1002/ana.26144.

[33]      Tabatabaee S, Rezania F, Alwedaie SMJ, Malekdar E, Badi Z, Tabatabaei SM, et al. Post COVID-19 vaccination Guillain-Barre syndrome: three cases. Hum Vaccin Immunother 2022;18:2045153. https://doi.org/10.1080/21645515.2022.2045153.

[34]      Karimi N, Boostani R, Fatehi F, Panahi A, Okhovat AA, Ziaadini B, et al. Guillain-Barre Syndrome and COVID-19 Vaccine: A Report of Nine Patients. BCN 2021;12:703–10. https://doi.org/10.32598/bcn.2021.3565.1.

[35]      Thant HL, Morgan R, Paese MM, Persaud T, Diaz J, Hurtado L. Guillain-Barré Syndrome After Ad26.COV2.S Vaccination. Am J Case Rep 2022;23:e935275-1-e935275-5. https://doi.org/10.12659/AJCR.935275.

[36]      Zubair AS, Bae JY, Desai K. Facial Diplegia Variant of Guillain-Barré Syndrome in Pregnancy Following COVID-19 Vaccination: A Case Report. Cureus 2022;14:e22341. https://doi.org/10.7759/cureus.22341.

[37]      Rossetti A, Gheihman G, O’Hare M, Kosowsky JM. Guillain-Barré Syndrome Presenting as Facial Diplegia after COVID-19 Vaccination: A Case Report. J Emerg Med 2021;61:e141–5. https://doi.org/10.1016/j.jemermed.2021.07.062.

[38]      Prasad A, Hurlburt G, Podury S, Tandon M, Kingree S, Sriwastava S. A Novel Case of Bifacial Diplegia Variant of Guillain-Barré Syndrome Following Janssen COVID-19 Vaccination. Neurol Int 2021;13. https://doi.org/10.3390/neurolint13030040.

[39]      Stefanou MI, Karachaliou E, Chondrogianni M, Moschovos C, Bakola E, Foska A, et al. Guillain-Barré syndrome and fulminant encephalomyelitis following Ad26.COV2.S vaccination: double jeopardy. Neurol Res Pract 2022;4:6. https://doi.org/10.1186/s42466-022-00172-1.

[40]      Castiglione JI, Crespo JM, Lecchini L, Silveira FO, Luis MB, Cotti N, et al. Bilateral facial palsy with paresthesias, variant of Guillain-Barré syndrome following COVID-19 vaccine: A case series of 9 patients. Neuromuscul Disord 2022;32:572–4. https://doi.org/10.1016/j.nmd.2022.05.003.

[41]      Lunn MP, Cornblath DR, Jacobs BC, Querol L, van Doorn PA, Hughes RA, et al. COVID-19 vaccine and Guillain-Barré syndrome: let’s not leap to associations. Brain 2021;144:357–60. https://doi.org/10.1093/brain/awaa444.

[42]      García-Grimshaw M, Michel-Chávez A, Vera-Zertuche JM, Galnares-Olalde JA, Hernández-Vanegas LE, Figueroa-Cucurachi M, et al. Guillain-Barré syndrome is infrequent among recipients of the BNT162b2 mRNA COVID-19 vaccine. Clin Immunol 2021;230:108818. https://doi.org/10.1016/j.clim.2021.108818.

[43]      Hanson KE, Goddard K, Lewis N, Fireman B, Myers TR, Bakshi N, et al. Incidence of Guillain-Barré Syndrome After COVID-19 Vaccination in the Vaccine Safety Datalink. JAMA Netw Open 2022;5:e228879–e228879. https://doi.org/10.1001/jamanetworkopen.2022.8879.

[44]      Osowicki J, Morgan H, Harris A, Crawford NW, Buttery JP, Kiers L. Guillain-Barré Syndrome in an Australian State Using Both mRNA and Adenovirus-Vector SARS-CoV-2 Vaccines. Ann Neurol 2021;90:856–8. https://doi.org/10.1002/ana.26218.

[45]      Keh RYS, Scanlon S, Datta-Nemdharry P, Donegan K, Cavanagh S, Foster M, et al. COVID-19 vaccination and Guillain-Barré syndrome: analyses using the National Immunoglobulin Database. Brain 2022:awac067. https://doi.org/10.1093/brain/awac067.

[46]      Dyer O. Covid-19: Regulators warn that rare Guillain-Barré cases may link to J&J and AstraZeneca vaccines. BMJ 2021;374:n1786. https://doi.org/10.1136/bmj.n1786.

[47]      Caress JB, Castoro RJ, Simmons Z, Scelsa SN, Lewis RA, Ahlawat A, et al. COVID-19-associated Guillain-Barré syndrome: The early pandemic experience. Muscle Nerve 2020;62:485–91. https://doi.org/10.1002/mus.27024.

[48]      Po ALW. Non-parenteral vaccines. BMJ 2004;329:62. https://doi.org/10.1136/bmj.329.7457.62.

[49]      Wan EYF, Chui CSL, Lai FTT, Chan EWY, Li X, Yan VKC, et al. Bell’s palsy following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: a case series and nested case-control study. Lancet Infect Dis 2022;22:64–72. https://doi.org/10.1016/S1473-3099(21)00451-5.

[50]      Poudel S, Nepali P, Baniya S, Shah S, Bogati S, Nepal G, et al. Bell’s palsy as a possible complication of mRNA-1273 (Moderna) vaccine against COVID-19. Ann Med Surg 2022;78:103897. https://doi.org/10.1016/j.amsu.2022.103897.

[51]      Cellina M, D’Arrigo A, Floridi C, Oliva G, Carrafiello G. Left Bell’s palsy following the first dose of mRNA-1273 SARS-CoV-2 vaccine: A case report. Clinical Imaging 2022;82:1–4. https://doi.org/10.1016/j.clinimag.2021.10.010.

[52]      Martin-Villares C, Vazquez-Feito A, Gonzalez-Gimeno MJ, de la Nogal-Fernandez B. Bell’s palsy following a single dose of mRNA SARS-CoV-2 vaccine: a case report. J Neurol 2022;269:47–8. https://doi.org/10.1007/s00415-021-10617-3.

[53]      Iftikhar H, Noor SMU, Masod M, Bashir K. Bell’s Palsy After 24 Hours of mRNA-1273 SARS CoV- 2 Vaccine. Cureus 2021;13:e15935. https://doi.org/10.7759/cureus.15935.

[54]      Pothiawala S. Bell’s Palsy After Second Dose of Moderna COVID-19 Vaccine: Coincidence or Causation? AML 2021;28. https://doi.org/10.15388/Amed.2021.28.2.7.

[55]      Burrows A, Bartholomew T, Rudd J, Walker D. Sequential contralateral facial nerve palsies following COVID-19 vaccination first and second doses. BMJ Case Rep 2021;14:e243829. https://doi.org/10.1136/bcr-2021-243829.

[56]      Obermann M, Krasniqi M, Ewers N, Fayad J, Haeberle U. Bell’s palsy following COVID-19 vaccination with high CSF antibody response. Neurol Sci 2021;42:4397–9. https://doi.org/10.1007/s10072-021-05496-5.

[57]      Mussatto CC, Sokol J, Alapati N. Bell’s palsy following COVID-19 vaccine administration in HIV+ patient. Am J Ophthalmol Case Rep 2022;25:101259. https://doi.org/10.1016/j.ajoc.2022.101259.

[58]      Colella G, Orlandi M, Cirillo N. Bell’s palsy following COVID-19 vaccination. J Neurol 2021;268:3589–91. https://doi.org/10.1007/s00415-021-10462-4.

[59]      Gómez de Terreros Caro G, Gil Díaz S, Pérez Alé M, Martínez Gimeno ML. Bell’s palsy following COVID-19 vaccination: a case report. Neurología (Engl Ed) 2021;36:567–8. https://doi.org/10.1016/j.nrleng.2021.04.002.

[60]      Tahir N, Koorapati G, Prasad S, Jeelani HM, Sherchan R, Shrestha J, et al. SARS-CoV-2 Vaccination-Induced Transverse Myelitis. Cureus 2021;13:e16624. https://doi.org/10.7759/cureus.16624.

[61]      Nishizawa Y, Hoshina Y, Baker V. Bell’s palsy following the Ad26.COV2.S COVID-19 vaccination. QJM 2021;114:657–8. https://doi.org/10.1093/qjmed/hcab143.

[62]      Burrows A, Bartholomew T, Rudd J, Walker D. Sequential contralateral facial nerve palsies following COVID-19 vaccination first and second doses. BMJ Case Reports 2021;14:e243829. https://doi.org/10.1136/bcr-2021-243829.

[63]      Tamaki A, Cabrera CI, Li S, Rabbani C, Thuener JE, Rezaee RP, et al. Incidence of Bell Palsy in Patients With COVID-19. JAMA Otolaryngology–Head & Neck Surgery 2021;147:767–8. https://doi.org/10.1001/jamaoto.2021.1266.

[64]      McCormick DavidP. Herpes-Simplex virus as cause of Bell’s palsy. Lancet 1972;299:937–9. https://doi.org/10.1016/S0140-6736(72)91499-7.

[65]      Tseng H-F, Sy LS, Ackerson BK, Hechter RC, Tartof SY, Haag M, et al. Safety of Quadrivalent Meningococcal Conjugate Vaccine in 11- to 21-Year-Olds. Pediatrics 2017;139:e20162084. https://doi.org/10.1542/peds.2016-2084.

[66]      Shibli R, Barnett O, Abu-Full Z, Gronich N, Najjar-Debbiny R, Doweck I, et al. Association between vaccination with the BNT162b2 mRNA COVID-19 vaccine and Bell’s palsy: a population-based study. Lancet Reg Health Eur 2021;11:100236. https://doi.org/10.1016/j.lanepe.2021.100236.

[67]      Wan EYF, Chui CSL, Ng VWS, Wang Y, Yan VKC, Lam ICH, et al. Messenger RNA Coronavirus Disease 2019 (COVID-19) Vaccination With BNT162b2 Increased Risk of Bell’s Palsy: A Nested Case-Control and Self-Controlled Case Series Study. Clin Infect Dis 2022:ciac460. https://doi.org/10.1093/cid/ciac460.

[68]      Frontera JA, Tamborska AA, Doheim MF, Garcia-Azorin D, Gezegen H, Guekht A, et al. Neurological Events Reported after COVID-19 Vaccines: An Analysis of Vaccine Adverse Event Reporting System. Ann Neurol 2022;91:756–71. https://doi.org/10.1002/ana.26339.

[69]      Chamberlin T. C. The Method of Multiple Working Hypotheses. Science 1890;ns-15:92–6. https://doi.org/10.1126/science.ns-15.366.92.

[70]      VAERS. Vaccine Adverse Event Reporting System. U.S. Department of Health & Human Services; 2021.

[71]      Ricke DO. Vaccines Associated Cardiac Adverse Events, including SARS-CoV-2 Myocarditis, Elevated Histamine Etiology Hypothesis. J Virol Viral Dis 2022;2. https://doi.org/10.54289/JVVD2200108.

[72]      Clark AK, Old EA, Malcangio M. Neuropathic pain and cytokines: current perspectives. J Pain Res 2013;6:803–14. https://doi.org/10.2147/JPR.S53660.

[73]      Zhang J-M, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin 2007;45:27–37. https://doi.org/10.1097/AIA.0b013e318034194e.

[74]      Thacker MA, Clark AK, Marchand F, McMahon SB. Pathophysiology of Peripheral Neuropathic Pain: Immune Cells and Molecules. Anesth Analg 2007;105. https://doi.org/10.1213/01.ane.0000275190.42912.37.

[75]      Yu J, Lou G-D, Yue J-X, Tang Y-Y, Hou W-W, Shou W-T, et al. Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy. Neurosci Bull 2013;29:261–9. https://doi.org/10.1007/s12264-013-1316-0.

[76]      Babazadeh A, Mohseni Afshar Z, Javanian M, Mohammadnia-Afrouzi M, Karkhah A, Masrour-Roudsari J, et al. Influenza Vaccination and Guillain-Barré Syndrome: Reality or Fear. J Transl Int Med 2019;7:137–42. https://doi.org/10.2478/jtim-2019-0028.

[77]      Sejvar JJ, Kohl KS, Gidudu J, Amato A, Bakshi N, Baxter R, et al. Guillain–Barré syndrome and Fisher syndrome: Case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine 2011;29:599–612. https://doi.org/10.1016/j.vaccine.2010.06.003.

[78]      Agrawal S, Verma K, Verma I, Gandhi J. Reactivation of Herpes Zoster Virus After COVID-19 Vaccination: Is There Any Association? Cureus 2022;14:e25195. https://doi.org/10.7759/cureus.25195.

[79]      Plüß M, Mese K, Kowallick JT, Schuster A, Tampe D, Tampe B. Case Report: Cytomegalovirus Reactivation and Pericarditis Following ChAdOx1 nCoV-19 Vaccination Against SARS-CoV-2. Front Immunol 2022;12. https://doi.org/10.3389/fimmu.2021.784145.

[80]      Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 2011;31:986–1000. https://doi.org/10.1161/ATVBAHA.110.207449.

[81]      Kawabata A. Prostaglandin E2 and Pain—An Update. Biol Pharm Bull 2011;34:1170–3. https://doi.org/10.1248/bpb.34.1170.

[82]      Soeiro T, Salvo F, Pariente A, Grandvuillemin A, Jonville-Béra A-P, Micallef J. Type I interferons as the potential mechanism linking mRNA COVID-19 vaccines to Bell’s palsy. Therapie 2021;76:365–7. https://doi.org/10.1016/j.therap.2021.03.005.

[83]      Fernandez PEL, Pereira JM, Risso IF, Rodrigues Silva PB, Freitas Barboza ICF, Silveira CGV, et al. Guillain-Barre syndrome following COVID-19 vaccines: A scoping review. Acta Neurol Scand 2022;145:393–8. https://doi.org/10.1111/ane.13575.

[84]      Goud R, Lufkin B, Duffy J, Whitaker B, Wong H-L, Liao J, et al. Risk of Guillain-Barré Syndrome Following Recombinant Zoster Vaccine in Medicare Beneficiaries. JAMA Intern Medi 2021;181:1623–30. https://doi.org/10.1001/jamainternmed.2021.6227.

[85]      Scendoni R, Petrelli C, Scaloni G, Logullo FO. Electromyoneurography and laboratory findings in a case of Guillain-Barré syndrome after second dose of Pfizer COVID-19 vaccine. Hum Vaccin Immunother 2021;17:4093–6. https://doi.org/10.1080/21645515.2021.1954826.

[86]      Hanson KE, Goddard K, Lewis N, Fireman B, Myers TR, Bakshi N, et al. Incidence of Guillain-Barré Syndrome After COVID-19 Vaccination in the Vaccine Safety Datalink. JAMA Network Open 2022;5:e228879–e228879. https://doi.org/10.1001/jamanetworkopen.2022.8879.

[87]      Röltgen K, Nielsen SCA, Silva O, Younes SF, Zaslavsky M, Costales C, et al. Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination. Cell 2022;185:1025-1040.e14. https://doi.org/10.1016/j.cell.2022.01.018.

[88]      Galdiero MR, Varricchi G, Seaf M, Marone G, Levi-Schaffer F, Marone G. Bidirectional Mast Cell–Eosinophil Interactions in Inflammatory Disorders and Cancer. Front Med 2017;4.

[89]      Rosa AC, Fantozzi R. The role of histamine in neurogenic inflammation. Br J Pharmacol 2013;170:38–45. https://doi.org/10.1111/bph.12266.

[90]      Dale HH, Laidlaw PP. The physiological action of beta-iminazolylethylamine. J Physiol 1910;41:318–44. https://doi.org/10.1113/jphysiol.1910.sp001406.

[91]      Ricke DO. Etiology Model for Elevated Histamine Levels Driving High Reactogenicity Vaccines (including COVID-19) Associated Menstrual Adverse Events. J Infect Dis Ther 2022:1–5. https://doi.org/10.4172/2332-0877.22.S3.002.

[92]      Malone RW, Tisdall P, Fremont-Smith P, Liu Y, Huang X-P, White KM, et al. COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms. Front Pharmacol 2021;12:216. https://doi.org/10.3389/fphar.2021.633680.

[93]      Tomera KM, Malone, Robert W., Kittah JK. Brief Report: Rapid Clinical Recovery from Severe COVID-19 with High Dose Famotidine and High Dose Celecoxib Adjuvant Therapy. Enliven: Pharmacovigilance and Drug Safety 2020;6:1–5.

[94]      Mather JF, Seip RL, McKay RG. Impact of Famotidine Use on Clinical Outcomes of Hospitalized Patients With COVID-19. Am J Gastroenterol 2020;115:1617–23. https://doi.org/10.14309/ajg.0000000000000832.

[95]      Sethia R, Prasad M, Mahapatra SJ, Nischal N, Soneja M, Garg P, et al. Efficacy of Famotidine for COVID-19: A Systematic Review and Meta-analysis. MedRxiv 2020:2020.09.28.20203463. https://doi.org/10.1101/2020.09.28.20203463.

[96]      Morán Blanco JI, Alvarenga Bonilla JA, Homma S, Suzuki K, Fremont-Smith P, Villar Gómez de Las Heras K. Antihistamines and azithromycin as a treatment for COVID-19 on primary health care - A retrospective observational study in elderly patients. Pulm Pharmacol Ther 2021;67:101989–101989. https://doi.org/10.1016/j.pupt.2021.101989.

[97]      Hogan II RB, Hogan III RB, Cannon T, Rappai M, Studdard J, Paul D, et al. Dual-histamine receptor blockade with cetirizine - famotidine reduces pulmonary symptoms in COVID-19 patients. Pulm Pharmacol Ther 2020;63:101942. https://doi.org/10.1016/j.pupt.2020.101942.

[98]      Otani IM, Anilkumar AA, Newbury RO, Bhagat M, Beppu LY, Dohil R, et al. Anti-IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis. J Allergy Clin Immunol 2013;131:1576–82. https://doi.org/10.1016/j.jaci.2013.02.042.

Tables

Table 1.  Co-occurrences of highest frequency vaccine associated pain adverse events from VAERS[70] (1990 to May 13, 2022).

Table 2.  Proportional Guillain-Barré syndrome compared to reactogenicity adverse events headache, fatigue, and pyrexia (fever); the proportions were normalized to highest observed proportion (e.g., FLUX).   The following vaccines with at least 40 reports of Guillain-Barré syndrome in VAERS[70] were included: COVID19, DTAP (diphtheria, pertussis, & tetanus), Influenza: FLU(H1N1), FLU3 (trivalent), FLU4 (quadivalent), FLUC4 (Flucelvax quadrivalent), FLUN3 (Flumist), FLUX (Influenza (seasonal) unknown manufacturer), FLUX(H1N1), HEP (hepatitis B), HEPA (hepatitis A), HEPAB (hepatitis B), HIBV (haemophilus), HPV2 (human papillomavirus), HPV4 (human papillomavirus type 4), IPV (inactivated poliovirus), MMR (measles, mumps, & rubella), MNQ (Menigococcal), PNC13 (Pneumococcal conjugate), PPV (Pneumococcal polysaccharide), TD (tetanus & diphtheria), TDAP (diphtheria, pertussis, & tetanus), TYP (typhoid), UNK (unknown), VARCEL (chickenpox Varicella), VARZOS (Herpes Zoster), and YF (yellow fever).   Enrichment was normalized to the vaccine (FLUX) with the highest ratio of adverse events: Guillain-Barré syndrome /reactogenicity adverse event for headache, fatigue, and pyrexia.

Table 3.  Proportional Bell’s palsy compared to reactogenicity adverse events headache, fatigue, and pyrexia (fever); the proportions were normalized to the highest observed proportion (e.g., COVID19).  The following vaccines with at least 40 reports of Bell’s palsy were included: COVID19, FLU4 (influenza quadivalent), UNK (unknown), and VARZOS (Herpes Zoster).  Enrichment was normalized to the vaccine (COVID19) with the highest ratio of adverse events: Bell’s palsy/reactogenicity adverse event for headache, fatigue, and pyrexia.