When a person experiences anaphylaxis—a sudden, severe, and potentially life-threatening allergic reaction—the allergen itself may not be the only factor at work. A study published in Clinical & Experimental Allergy examined 16,915 real-world cases from the European Anaphylaxis Registry (collected between 2007 and 2024) to investigate how “cofactors” influence these emergencies. Cofactors are circumstances or conditions—such as exercising, drinking alcohol, or being sick—that may change how the body responds to an allergen. Clinicians reported at least one suspected cofactor in nearly half (49%) of all reviewed cases, suggesting that everyday circumstances may play an important role in allergic reactions.
The types of cofactors people encounter change significantly with age. Suspected cofactors were reported in only 26% of children and teens, compared to 59% of adults. Even after excluding medications, which are more commonly used by adults, 36% of adults still had at least one suspected cofactor. For adults, medications (41%) and exercise (27%) topped the list, while physical activity was the single most commonly reported factor for kids, appearing in 19% of childhood reactions. Other suspected influences included emotional stress, alcohol consumption, acute infections, lack of sleep, and menstruation.
Different allergens also appear to interact with these background factors in distinct ways. Exercise was frequently linked to both food and insect sting reactions, but its association with wheat allergy was particularly striking. In adults with wheat-induced anaphylaxis, physical activity was reported as a suspected cofactor in 80% of cases. The researchers noted that this could reflect the prevalence of wheat-dependent exercise-induced anaphylaxis, although greater physician awareness of this particular relationship may also contribute to the finding. Children, on the other hand, rarely had exercise identified as a suspected cofactor in drug-induced reactions; instead, acute infections and other medications were the most commonly reported cofactors when children reacted to medicines.
When examining reaction severity, the researchers found that having multiple suspected cofactors was generally associated with worse outcomes. As the number of reported cofactors increased, so did the likelihood of reactions involving multiple body systems or receiving a higher severity rating under established clinical classification systems. However, these associations were generally modest and were not consistent across every severity measure or type of allergen. Previous research suggests that cofactors may lower the amount of allergen needed to provoke a reaction or increase its severity, although this registry study could not directly determine whether cofactors lowered reaction thresholds. Importantly, severe and life-threatening reactions can occur even when no cofactors are present.
A few specific associations stood out as particularly consistent. Among children, having an acute infection at the time of anaphylaxis was associated with more severe reactions across all three measures used by the researchers. For adults experiencing food-induced anaphylaxis, alcohol consumption was similarly associated with greater severity. Certain cardiovascular medications—including beta-blockers, ACE inhibitors, and statins—were also linked to more severe outcomes, particularly in drug-induced and insect sting reactions. However, the researchers cautioned that these medication findings were based on analyses that did not adjust for underlying cardiovascular disease, making it difficult to separate the potential effects of the drugs from those of the conditions being treated. Although some of these medications may influence immune cell activity or the body’s response to anaphylaxis, the study did not establish the biological mechanisms responsible.
The study also uncovered an important association involving timing. Suspected cofactors were more frequently reported when a longer interval passed between allergen exposure and the onset of symptoms. This pattern was especially pronounced in food-induced anaphylaxis across all age groups. The researchers highlighted reactions developing more than an hour after food exposure as situations in which clinicians should pay particular attention to possible cofactors. However, the findings do not establish that cofactors themselves caused the delayed reactions.
Recognizing these outside influences may offer practical ways for people with allergies to reduce their risks. The authors emphasized that “routine inquiry about cofactors should form part of the clinical assessment, with particular attention to food-induced reactions of delayed onset.”
