Soon after administration of the first COVID-19 vaccine began in the United Kingdom, two patients experienced apparent anaphylaxis, raising fears that many more would follow. While those worries were unfounded—additional reports were rare as millions of patients received the Pfizer-BioNTech vaccine and the second mRNA vaccine, from Moderna—concerns about allergic reactions, and how to manage them, persist. During “Allergic Reactions to COVID-19 Vaccines: Separating Fact from Fiction,” a session at the American Academy of Allergy Asthma & Immunology's (AAAAI) annual meeting, held virtually in February, experts offered up-to-date advice on this issue.
A range of symptoms soon after COVID-19 vaccination have been characterized as potentially allergic, said John M. Kelso, MD. He reviewed data published in the Jan. 15 MMWR on the Pfizer-BioNTech vaccine detailing the types of reactions reported and characterized as anaphylaxis, including rashes, a sense of throat closure, urticaria, facial swelling, shortness of breath, and wheezing.
“Although we have a lot of definitions for anaphylaxis, I think we can kind of generally agree that an anaphylaxis reaction usually involves urticaria, and some combination of respiratory or cardiovascular symptoms, but I think it's important, particularly having looked at that list, that there are other reactions that can mimic anaphylaxis,” said Dr. Kelso, who is a clinical professor of pediatrics and internal medicine at the University of California, San Diego, and faculty at the Scripps Clinic.
He noted that vasovagal reactions can also cause lightheadedness or syncope but are typically preceded by bradycardia and pallor, as opposed to the tachycardia and flushing usually seen with anaphylaxis. In addition, vocal cord spasm can cause stridor and dyspnea, and panic attacks and anxiety can cause a feeling of swelling in the throat when none is present (globus sensation), palpitations, dyspnea, and other symptoms, he said.
“In talking to these patients after the fact, when we see them in clinic, both patients and providers are often reluctant to believe that what happened to them was not an allergic reaction because they saw or felt something,” said Dr. Kelso. “And I found it useful to just remind people that there are other common circumstances where people may have had a physical reaction that was not an allergic reaction.”
Dr. Kelso noted that anaphylactic reactions to COVID-19 would seem to be “a little perplexing” because almost all IgE antibody is generated against proteins and requires some previous exposure to be sensitized. “All these reactions thus far have been reported after first doses of the vaccine that nobody's ever been exposed to before, and also the vaccines do not contain any protein, so they don't seem like likely candidates to be causing anaphylaxis reactions,” he said.
Most of the attention regarding a potential causative agent has focused on polyethylene glycol (PEG), which functions as one of the excipients in the mRNA vaccines. Dr. Kelso explained that PEG is widely used not only in medications, including corticosteroids and progesterone, but also in bowel preps and laxatives, cosmetics, and foods. While PEG has not been used in any vaccine before COVID-19, there is speculation that these types of earlier exposure could explain prior sensitization. However, Dr. Kelso pointed out that the amount of PEG in the mRNA COVID-19 vaccines is extremely low compared to the amount in medications that have triggered allergic reactions.
“Some of these reports are related to injections of methylprednisolone acetate [which contains PEG 3350 in a concentration of 29 mg/mL], and just by comparison, the Pfizer COVID vaccine contains 0.05 milligrams of PEG, so even in somebody, the rare patient, who's PEG allergic, we still don't know if there's enough PEG in the vaccine to actually cause a reaction,” Dr. Kelso said. “To date, there have not been any confirmed cases where somebody had an anaphylaxis reaction to the vaccine, a positive vaccine skin test, and where it's been determined that PEG is the actual allergen.”
Elizabeth J. Phillips, MD, agreed that primary PEG anaphylaxis is extremely rare in general and not often reported in the literature. “It's hard to know how rare, but one in a million probably would not be out of keeping, given that most allergists would say even looking for this, they fail to see more than five to 10 in their entire 40- or 50-year practices,” said Dr. Phillips, who is the John A. Oates Chair in Clinical Research and professor of medicine and pharmacology and of pathology, microbiology, and immunology at the Center for Drug Safety and Immunology at Vanderbilt University Medical Center in Nashville, Tenn. She added that although these reactions are rare, it is noteworthy that patients with true anaphylaxis to PEG can develop anaphylaxis to micrograms injected under their skin as part of a skin testing procedure.
Dr. Phillips outlined differences that have emerged between patients with PEG anaphylaxis and those with reported anaphylaxis to mRNA COVID-19 vaccines. For example, PEG anaphylaxis appears to be more equally split across men and women, and those with underlying atopy are not overrepresented, she noted. In contrast, anaphylaxis with the mRNA COVID-19 vaccines is most significantly apparent in women and those with underlying atopic tendency. Also, milder versions of immediate reactions associated with the COVID-19 mRNA vaccines appear to have resolved without treatment or with antihistamines, while patients with PEG anaphylaxis rapidly escalate to needing epinephrine and tend to worsen rapidly on repeated exposure, Dr. Phillips said.
Questions that remain to be answered include whether the excipients in the COVID-19 vaccines are actually the cause of anaphylaxis or whether any of the reactions associated with the mRNA COVID-19 vaccines are IgE-mediated, Dr. Phillips said. However, she stressed that it is important to instill public confidence by using safe and proactive approaches to risk-stratify patients and get most people vaccinated without delay while experts learn more.
Matthew Greenhawt, MD, MBA, MSc, recommended that clinicians carefully consider whether a previous excipient reaction should disqualify a patient from vaccination. “Is something safe until proven dangerous, or dangerous until proven safe?” he asked. “You could say that the former might be irresponsible, but I would say that the latter sets up a standard that becomes very, very, very hard to disprove.”
Dr. Greenhawt, who is an associate professor of pediatrics in the section of allergy and immunology and director of the food challenge unit at Children's Hospital Colorado and the University of Colorado School of Medicine in Denver, was a coauthor on a recent modeling study, in press at the Journal of Allergy and Clinical Immunology: In Practice and published online March 9, that compared universal COVID-19 vaccination with restricted vaccination based on a history of anaphylaxis. The former strategy was associated with a cost savings of $503 million and 7,607 lives saved in a single year and remained cost-effective until the rate of anaphylaxis from the vaccine reached 8,000 cases per million. These results, he said, indicate that deferring COVID-19 vaccination based on PEG sensitization or other reasons could have serious health consequences.
“I'm not saying don't do it. I'm just saying be aware of what you are choosing and the values and the implications of that process,” he said. “Just understand there are costs that you might not have thought about from this.”
Regarding whether to give a second COVID-19 vaccine dose after a reaction to the first, Dr. Greenhawt said not enough information is available yet to make an informed decision, given incomplete data on whether these reactions are IgE-mediated and whether protection from the first dose, particularly in the setting of having had previous COVID-19 infection, is good enough to forgo the second, among other issues.
“You can make a theoretical determination of when it is safe to give the next dose, but … that risk determination is going to be different based on who you are and who you're seeing,” he said. “The biggest advice I can give here is to please just talk to your patients about what they want. I can't emphasize that enough.”
The CDC guidance on COVID-19 vaccination places patients who have had a history of other allergic reactions in the “green” category, Dr. Kelso explained. “Even if you've had a history of anaphylaxis, a serious allergic reaction due to any cause, you can still get your vaccine,” he said. “You should just be observed for 30 minutes afterwards, instead of 15 minutes afterwards, because we really don't have any reason to believe that even serious allergic reactions to other substances somehow puts you at risk for this.”
The CDC's “yellow” category includes patients who have had an immediate allergic reaction to some other vaccine or injectable medicine, including those that might have contained PEG. The CDC indicates that patients in this group could be considered for referral to an allergist but could also be vaccinated and observed for 30 minutes, which is the course Dr. Kelso recommends. The “red” category, meanwhile, notes that vaccination is contraindicated in patients who have had a severe or immediate allergic reaction to the COVID-19 vaccine or any of its components.
“If you've had an allergic reaction to PEG or its cousin polysorbate, which is structurally related, that could be a reason to say you're not going to vaccinate that person. But importantly, [the CDC also recommends that clinicians] consider a referral to an allergist-immunologist, and that's absolutely what I would advocate,” Dr. Kelso said.
While physicians and other clinicians overseeing vaccination clinics should certainly recognize and treat anaphylaxis after vaccine administration, Dr. Kelso stressed, they should also be aware of the differential diagnosis and carefully record vital signs and physical exam findings, including taking photos of any skin findings. This can help clearly differentiate between patients looking a little red versus having frank urticarial lesions, experiencing the sensation of a lump in the throat versus having documented swelling, or being short of breath versus actually wheezing, he said.
If the patient is seen in an ED or urgent care setting, getting a mast cell tryptase level within a couple of hours of a reaction can be helpful to identify anaphylaxis, Dr. Kelso said. “And then importantly, whether it's vaccine sites, urgent care centers, emergency departments where these patients are sent after these events, rather than the patient simply being told that they're allergic and they can't get a second dose, we would encourage our colleagues to route these patients to be seen in an allergy clinic, where we can try to sort this out,” he said.