Adverse Events of Special Interest (AESI) and related risks

In investigating adverse events––in particular, serious events of special interest––it is important to consider the possibility that the event may be associated with, or be caused by other factors, such as diseases, medications being used, or other previously administered vaccines. 

In order to facilitate the evaluation of events of special interest, the following provides a summary of the main factors to consider, in this example for Guillain-Barré Syndrome (GBS):

Definition: Immune-mediated disease resulting from the production of autoimmune antibodies and/or inflammatory cells, which cross-react with epitopes of the peripheral nervous system, causing demyelination and/or axonal injury (1).

Diseases: Autoimmune antibodies can be formed by a variety of antigenic stimuli, such as bacterial or viral infection, with a history of an infectious disease (diarrhea or respiratory disease) in the days or weeks before neurological signs appear. Among the associated infectious agents are the gastrointestinal bacterium Campylobacter jejuni, the influenza virus Mycoplasma pneumoniae, the human immunodeficiency virus, Epstein-Barr virus, cytomegaloviruses, and Zika.

In rare cases, an association with surgical procedures and with some neoplasms, particularly Hodgkin's disease and other lymphomas, has also been observed (1, 2).

Medications: GBS has most often been associated with the use of penicillin and antispasmodic medications, and less frequently with the use of oral contraceptives. Though not involving definite cause-and-effect relationships, there are reports of cases related to streptokinase, isotretinoin, danazol, captopril, gold, heroin, cyclosporin A, and fluoroquinolones (3, 4).

Vaccines: There is evidence of GBS following administration of the pH1N1 pandemic virus vaccine, with no increased risk associated with adjuvant vaccines. Studies evaluating the risk of GBS with new influenza vaccine formulations have not consistently demonstrated an increase in marginal risk. Evidence of the link between GBS and vaccines against measles, rubella, and mumps (MMR), herpes zoster (VZV), hepatitis A/B, human papillomavirus (HPV), diphtheria-tetanus, and acellular pertussis (DTaP), as well as meningococcal vaccines, may be insufficient to either confirm or rule out a causal relationship. GBS has been temporally associated with numerous vaccines; however, this temporal association must be differentiated from causation (1, 5).

Sources: 

1. Sejvar J, Kohl K, Gidudu J, et al. Guillain-Barré Syndrome and Fisher syndrome: Case definitions and guidelines for collection, analysis, and presentation of immunization safety data, Vaccine, Volume 29, Issue 3, 2011, Pages 599–612, https://doi.org/10.1016/j.vaccine.2010.06.003
2. Center for Disease Control and Prevention. Zika Virus. Zika and Guillain-Barré Syndrome. Available at: https://www.cdc.gov/zika/healtheffects/gbs-qa.html
3. Andary MT, Medscape. Zika and Guillain-Barré Syndrome. Available at: https://emedicine.medscape.com/article/315632-overview#a2
4. Rizawati et al. J Clin Nephrol. Guillain-Barré Syndrome Associated with Cyclosporine A. Ren Care 2016, 2:009 Volume 2 | Issue 1. https://clinmedjournals.org/articles/jcnrc/journal-of-clinical-nephrology-and-renalcare-jcnrc-2-pdf.
5. Barbara Law. Safety Platform for Emergency vACcines SO2- D2.5.2.1 - AESI Case Definition Companion Guide for 1st Tier AESI Guillain-Barré and Miller Fisher Syndromes Work Package: WP2 Standards and tools V1.0 – February 9th, 2021, Nature: Report | Diss. Level: Public. https://brightoncollaboration.us/wpcontent/uploads/2021/03/SPEAC_D2.5.2.1-GBS-Case-Definition-Companion-0_format12062-

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