Stress-Related COVID Vaccine Reactions May Mimic Anaphylaxis

SAN ANTONIO — Many reported anaphylactic reactions to COVID-19 vaccination may in fact be attributable to vaccine-induced immunization stress-related response (ISRR), suggested findings from a small study presented here.

Cases of ISRR — a non-allergic condition that mimics many of the symptoms of anaphylaxis — may help explain why rare anaphylactic reactions to mRNA COVID vaccines have been somewhat higher than those reported for conventional vaccines, according to Muhammad Khalid, MD, a clinical fellow at the National Institute of Allergy and Infectious Diseases.

In an interview with MedPage Today at the American Academy of Allergy, Asthma & Immunology annual meeting, Khalid said ISRR appears to be a widely underrecognized anaphylaxis mimic, and he suggested that the true rate of anaphylaxis following vaccination with mRNA COVID vaccines may be lower than reported.

The double-blind study included 16 adults (15 women and 1 man) who had experienced systemic allergic reactions soon after receiving their first dose of Pfizer/BioNTech or Moderna’s COVID-19 vaccines.

Participants received a second dose of the Pfizer vaccine or a placebo shot on the first of two consecutive days, with the other shot given on the following day. All vaccinations occurred at the intensive care unit of the NIH Clinical Center in Bethesda, Maryland, under close medical supervision and monitoring.

Three of the 16 patients experienced an allergic reaction after receiving the second dose of mRNA vaccine (one mild and two moderate) while none developed allergic reactions after receiving the placebo shot. The allergic reactions occurred a median of 4 minutes after vaccination.

However, non-allergic reactions consistent with ISRR occurred in 11 study participants receiving the placebo shot and nine after receipt of the mRNA vaccine, with a median symptom onset of 3 minutes after delivery. Non-allergic symptoms included numbness, tingling, dizziness, throat tightness, dysphagia, and hypertension, which have all been linked to ISRR, Khalid said.

Thirteen of the 16 study participants went on to receive a third, unblinded booster dose of the mRNA vaccine in the supervised medical setting, and 10 developed symptoms consistent with ISRR, with a median symptom onset of 7 minutes.

Khalid said the COVID-19 pandemic and the public health push for universal vaccination once vaccines became available represented something of a perfect storm for anxiety-related reactions that are not directly related to the vaccine product.

“People were already under stress due to COVID, and they were getting a brand new vaccine and hearing about adverse reactions,” Khalid said. “All of this created an atmosphere where these very real symptoms resulting in real distress were occurring, which were unrelated to the vaccine itself.”

In a 2019 report, the World Health Organization (WHO) first proposed the term “immunization-stress related response” to refer to “any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of the vaccine.”

The WHO report identified four overlapping groups of reactions as ISRRs, including acute anxiety and stress responses, vasovagal reactions, mass psychogenic illness, and functional neurological disorders.

Khalid said several common symptoms associated with non-allergic ISRR reactions mimic allergic reactions, including tingling, numbness, and tightening of the throat.

But unlike allergic reactions these symptoms do not usually get worse with time, he said.

Rapid elevation in blood pressure and heart rate are also a typical symptom with ISRR reactions, while blood pressure tends to decrease in people experiencing allergic reactions to vaccine, he said.

The WHO report highlights common differences in presentation, including:

• Onset: Anaphylaxis reactions typically occur 5 minutes after immunization, but may be delayed up to 60 minutes, while general acute stress responses can occur before, during, or shortly after (<5 minutes) immunization.
• Skin: Common anaphylaxis reactions include generalized urticaria or erythema, angioedema, generalized pruritis with or without skin rash, localized injection site urticaria and red/itchy eyes. Reactions common in acute stress response more typically involve pale, sweaty, cold, or clammy skin.
• Respiratory: Common anaphylaxis respiratory symptoms include persistent cough, noisy breathing and airway constriction, wheeze, stridor and — in severe cases — respiratory arrest. Hyperventilation is more common in ISRR.
• Cardiovascular: Anaphylaxis reactions typically involve elevated heart rate with a drop in blood pressure, while blood pressure tends to spike with ISRR.

Khalid said that use of rescue epinephrine can be reduced by carefully monitoring patient reactions, although he acknowledged the challenges in distinguishing between vaccine-related anaphylaxis and ISRR.