Transient Eyelid Edema Following COVID-19 Vaccination

To the Editor:

Vaccinations have provided immunological protection against pathogens for nearly 100 years and while uncommon, complications of the eyes and ocular adnexa can occur with varied presentation.¹ Anaphylactic reactions are known to present with ocular symptoms, such as eyelid puffiness, but are typically accompanied by systemic inflammatory symptoms.¹ Separately, several vaccines are known to cause adverse eyelid effects that are distinct from anaphylactic reactions. Periorbital swelling with ocular vaccinia is a known complication of the smallpox vaccine, with 3.6 per 100,000 vaccines presenting with periorbital edema.² Additionally, transient eyelid edema as a symptom of ocular respiratory syndrome was reported with the influenza vaccine in the early 2000s.³ Studies demonstrated that the peak incidence of ocular respiratory syndrome was 46 per 100,000 patients and of those, 18% presented with edema, primarily of the eyelid.³

The Pfizer-BioNTech COVID-19 vaccine was issued an emergency use authorization on December 11, 2020.⁴ It has been demonstrated to have a 95% efficacy following the second dose.⁴ However, adverse reactions have been reported. In a review of the Vaccine Adverse Events Reporting System data, it was found that isolated ocular reactions to the COVID-19 vaccine are uncommon, with only 46 reported cases, and of those, 34 (74%) are associated with the eyelid.¹ We describe a series of 3 female patients who presented with spontaneous unilateral eyelid edema and erythema with otherwise normal ocular exams following administration of the Pfizer COVID-19 vaccine.

In our 3 patients, average age was 39.3 years old (range: 32–43 years), and all patients had no ocular or medical history. They each presented on day 1 or 2 following their first or second dose of the Pfizer COVID-19 vaccine. Each patient presented with unilateral upper greater than lower eyelid edema and erythema without other associated ocular, adnexal, or systemic findings (Fig.). The 3 patients were treated with observation, antihistamines, and oral steroids, respectively, and each patient had full resolution of their symptoms in 1–2 days without sequela.

Figure.

Mild, unilateral, upper greater than lower, eyelid erythema, and edema presenting 1 day after the first dose of the SARS-CoV-2 Pfizer mRNA Vaccination. No additional ocular or adnexal signs or symptoms were observed. This patient’s eyelid edema and erythema resolved in 1 day with antihistamine treatment and the patient experienced no known ocular sequela.

We acknowledge that the precise etiology and pathophysiology of these patients’ spontaneous eyelid edema is unknown and cannot be definitively associated with the COVID-19 vaccination. However, there are proposed immunologic mechanisms for adverse vaccine-related events, including complement system activation and molecular mimicry.⁵ In normal immunology, the complement system within tear film is an important part of the closed eye’s immunological defense, and its activation results in an increase in cytokine inflammatory mediators.⁶ It has been suggested that complement mediators in the tear film are the result of the leakage of plasma.⁶ Studies have demonstrated that the complement system has a critical role in the pathogenicity of COVID-19.⁷ In our patients, it is possible that the COVID-19 vaccine caused complement activation that increased complement mediators within the plasma and tear film, resulting in eyelid edema.

Alternatively, the COVID 19 vaccine may trigger a specific immune response pathway through molecular mimicry. There are a number of SARS-CoV-2 proteins that exhibit cross reactivity with human proteins and could result in autoimmunity.⁷ However, it is not plausible that an adaptive cross-reactive immune response to SARS-CoV-2 spike protein receptor-binding domain could be manifest as soon as 1 day after administration of mRNA encoding it. It has also been suggested that antibodies to the spike glycoprotein of the mRNA vaccines can elicit an acute autoimmune response.⁷ Specific stimuli that initiate reactivation of autoimmune responses in diseases such as thyroid eye disease have not been identified, and it has been suggested that molecular mimicry has a role in the development of such diseases.⁸ We hypothesize that the patients’ eyelid edema is the result of a reactivation of an autoimmune response that is triggered by the mRNA vaccine.

These 3 cases may represent a relatively uncommon reaction related to the vaccine that was either self-limited or resolved with minimal treatment. In similar cases, appropriate workup should be performed to rule out masquerading entities, but it may assist the clinician to appreciate this potentially self-limited, vaccine-related entity in the appropriate context. To our knowledge, this is the first report of unilateral, spontaneous eyelid edema following vaccination with the Pfizer COVID 19 mRNA vaccine. It is important for the ophthalmologic and medical community to be aware that such ocular reactions do occur and future studies with adequate powering should be performed to further characterize and understand this process.