key: cord-0852220-54jy3pvu
authors: Watts, Melissa M.; Maurer, Laura E.; Grammer, Leslie C.; Saltoun, Carol A.; Stevens, Whitney W.
title: Delayed angioedema following SARS-CoV-2 mRNA vaccine administration
date: 2021-10-23
journal: Ann Allergy Asthma Immunol
DOI: 10.1016/j.anai.2021.10.021
sha: 5b001726979879f8fe2f84373894fdfaffe2761b
doc_id: 852220
cord_uid: 54jy3pvu

nan

The COVID-19 pandemic has led to millions of deaths worldwide and continues to be a public health threat. Administration of COVID-19 vaccines safely and markedly decreases the chance of contracting SARS-CoV-2 and prevents severe COVID-19. Their widespread use is imperative to ending the pandemic. Since their implementation, various adverse reactions to the mRNA COVID-19 vaccines have been reported with the most common being delayed cutaneous reactions, and more rarely anaphylaxis 1,2,3 . Here, we present 3 cases of delayed angioedema following mRNA COVID-19 vaccination ( Table 1) :

Case 1. A 21-year-old male with a history of chronic rhinitis tolerated his first Pfizer-BioNTech COVID-19 mRNA vaccine without adverse symptoms. Two and a half days following his second dose (given 3 weeks later), he developed erythematous plaques and wheals on his thigh with subjective tongue swelling. The rash was evanescent but persisted despite antihistamine treatment, becoming more diffuse over 30 hours. Five days following his second dose, he developed marked swelling of his lips with dysphagia prompting evaluation in the emergency department (ED), where he was found to be normotensive and tachycardic. Physical exam was notable for an urticarial rash on his neck and face as well as swelling of the posterior pharynx, tongue, upper lip, and periorbital area. In the ED, he was given 0.3mg intramuscular (IM) epinephrine, 125mg intravenous (IV) methylprednisolone, 20mg IV famotidine, 50mg IV diphenhydramine, and 10mg oral (PO) cetirizine. The patient's angioedema began to improve within 8 hours and completely resolved within 24 hours. He denied prior episodes of angioedema and reported no further episodes in the subsequent 7 months.

Case 2. A 33-year-old male with a history of type 1 diabetes mellitus, allergic rhinitis, peanut allergy, and eosinophilic esophagitis tolerated his first Pfizer-BioNTech COVID-19 mRNA vaccine without immediate adverse symptoms. Thirty hours later, he developed throat tightness, dysphagia, and dyspnea. He self-administered 0.3mg IM epinephrine and presented to the ED where he was hypertensive and tachycardic. Physical exam revealed dysphonia, dyspnea, and tripoding. Flexible laryngoscopy revealed grape-size uvular swelling and edema of the false vocal folds. He received another dose of 0.3mg IM epinephrine, 50mg IV diphenhydramine, and 125mg IV methylprednisolone. Due to the severity of his symptoms, he was started on a continuous IV epinephrine infusion that was weaned overnight as angioedema improved. Serum tryptase drawn in the ED was normal. The patient denied ingestion of peanut prior to symptom onset and had no prior history of angioedema. He received his second Pfizer-BioNTech vaccine 6 months after this reaction without complications. He reported no further episodes of angioedema in the subsequent 9 months. Anaphylaxis to mRNA COVID-19 vaccines is estimated to occur in 2.5-11.1 cases per million doses 1,4,5 . In these cases, diffuse erythematous rash, generalized urticaria, angioedema, wheezing, dyspnea, hypotension, nausea, and vomiting were typically observed within 15-30 minutes of administration 2,4,5,6 . In contrast, the mean time to symptom development in our three cases was 39 hours and, when available, tryptase collected at the time of symptoms was within the normal range. Urticaria has been reported to develop within 1-3 days following vaccination but, in these reports, there was no association with angioedema 3,7 . Delayed local cutaneous reactions with erythema, induration, and tenderness developed approximately 8 days and 2 days following first and second vaccinations, respectively, have also been described 3, 7 .

However, our cases did not have involvement at the injection site.

Altogether, these cases were disparate in terms of gender, race, ethnicity, and atopic history. All patients denied a prior history of angioedema and could not identify an alternative trigger immediately prior to symptom onset. The only commonality among these patients was the administration of an mRNA COVID-19 vaccine hours or days prior to the onset of symptoms. This suggests, but by no means proves causality between the vaccine administration and development of delayed urticaria and angioedema. The lifetime prevalence of urticaria is about 9% 8 , and it is estimated that approximately 1% of the general population is likely to experience an episode of angioedema 9 . We thus cannot exclude the possibility that the episodes of angioedema reported here were simply the incident case of chronic spontaneous angioedema in each of these patients, however so far, none have had a second episode.

In summary, we report 3 distinct cases of angioedema that occurred within days of receiving a mRNA COVID-19 vaccine that were severe enough to warrant an ED visit. From the clinical history, no factor was identified that could have predicted that the angioedema (or the severity) would develop in each case. Fortunately, all patients were successfully treated, and no deaths occurred. Such cases of delayed angioedema appear to be rare and interestingly, patient 2 received the second vaccine dose without complications or delayed angioedema. While patients and clinicians need to be aware of the risk of adverse reactions, including the possibility of delayed angioedema following administration of a novel mRNA COVID-19 vaccine, the benefits of receiving the COVID-19 vaccine continue to outweigh the risk of a potential adverse reaction occurring for most individuals. 

Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-based study of 414 cases

Acute Allergic Reactions to mRNA COVID-19 Vaccines

Reports of Anaphylaxis After Receipt of mRNA COVID-19 Vaccines in the US

Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine -United States

Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2

Urticaria: A comprehensive review: Epidemiology, diagnosis, and work-up

Presentation, diagnosis and treatment of angioedema without wheals: a retrospective analysis of a cohort of 1058 patients

We would like to acknowledge Drs. Bruce Bochner, Paul Greenberger, Fei Li Kuang, KrisMcGrath, Gayatri Patel, and Anju Peters for their assistance with this manuscript and discussions of the clinical cases.

Chronic rhinitis, no prior history of angioedema