Female patients disproportionately represented among COVID-19 vaccine allergy referrals

Female patients were disproportionately referred to allergy clinics due to concerns about possible reactions to COVID-19 vaccination compared with male patients in Hong Kong, according to a letter published in Asthma.

These ratios were significant for all ages and whether the referrals were before or after the vaccine was administered, Valerie Chiang, MBBS, of the division of clinical immunology, department of pathology, Queen Mary Hospital, Hong Kong, and colleagues wrote.

The researchers examined the male-to-female ratio of 3,201 consecutive patients who were referred to the Vaccine Allergy Safety (VAS)-Track Pathway.

These patients included those who were pre-vaccine, meaning they had a history of anaphylaxis or severe and immediate types of reactions to multiple classes of drugs, and those who were post-vaccine, meaning they had a history of suspected hypersensitivity reactions after previous vaccination for COVID-19.

Study results

While females made up 54.4% of the Hong Kong population in its Population Census Data, they represented 74.8% of the referrals to the VAS-Track Pathway (P < .001), including 74% of the pre-vaccine and 76.7% of the post-vaccine referrals. These differences were consistent across age groups.

For example, females made up 49.3% of those aged 15 to 24 years in the Population Census Data, but represented 59.6% of all referred patients, including 65.2% of the pre-vaccine and 55.7% of the post-vaccine referrals.

In the group of people aged 35 to 44 years, women made up 60% of the population, 76.6% of all referrals, and 73.3% of all pre-vaccine and 82.6% of all post-vaccine referrals.

Among those people aged 65 years and older, women accounted for 53% of the population, 68.3% of all referrals, and 70.1% of all pre-vaccine and 63.2% of all post-vaccine referrals.

But when allergists assessed suspected allergies to differentiate them from reactogenic symptoms and confirmed or excluded them via vaccine provocation tests, there were no significant differences in COVID-19 allergies based on sex across all age groups.

Overall, 12.6% of the referrals led to a confirmed or possible allergy, including 11.2% of the males and 13.1% of the females. Specific results included 8.5% of those aged 15 to 24 years, with 6.1% of the males and 10.3% of the females; 11.8% of those aged 35 to 44 years, with 9.7% of the men and 12.5% of the women; and 12.1% of those aged 65 years and older, with 11.9% of the men and 12.2% of the women.

Possible causes

After suspecting that a higher prevalence of urticaria among female patients may have driven these differences, the researchers excluded patients with a history of urticaria from the study, yet still found that females accounted for 77% of the referrals but only 54.4% of the general population (P < .001).

Females often report more frequent and severe reactions to vaccines and drugs, the researchers noted, with well documented, multifactorial mechanisms including sex, gender and comorbidities driving these differences.

For example, lower body weights and body surface area totals lead to higher blood concentrations, longer elimination times and possible augmented reactogenicity among females, the researchers said.

Also, the researchers continued, females have stronger immune responses, while differences linked to the X chromosome, epigenetics and microbiota may affect immunoregulation as well.

Psychological, social and cultural influences also may play a role, with females experiencing lower tolerance and greater stress and anxiety due to mucocutaneous manifestations on the face or body, the researchers suggested.

Females additionally are more proactive in seeking out health information, which may lead them to be more susceptible to misinformation and subsequent misdiagnoses for vaccine allergies, the researchers continued.

Finally, the researchers said, asthma and atopic dermatitis are more common among females and may be misdiagnosed as vaccine allergies during coincidental flares.

The researchers emphasized that genuine allergies related to COVID-19 vaccines are extremely rare, with no significant differences between the sexes in terms of vaccination outcomes. However, they recommended further studies into why women experience higher rates of suspected allergic reactions.