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Partners in crime: the enigma of two-culprit allergic reactions

When exercise and allergy collide.

20-year-old August* perplexed his doctor. He often ate spaghetti for dinner, with no troubles. He could eat focaccia during lunch at school, and had no symptoms whilst sitting in afternoon classes. However, on one occasion he ate a jam sandwich and sprinted home in the cool breeze. Soon, like a switch had been flipped, hives developed all over his body. He felt his throat closing in and had trouble breathing. Despite wheat never once being his enemy, he was now experiencing anaphylaxis. 

Within the field of immunology, the understanding of allergic processes is incomplete; amongst the non-medical community, it is even more limited. Dr Sameer Malik, clinical immunologist at Concord Hospital, says that patients often feel confused. “It is really scary and frustrating,” he claims, “as often allergic reactions only occur in certain scenarios, or develop later in life.” Even for doctors, allergies are unpredictable, as they “don’t always follow the way you think [they] should.” 

There is emerging evidence that anaphylaxis can occur after exposure to a combination of triggers. Foods may need an accomplice, known as a cofactor, to pull the trigger. Common amplifying cofactors include exercise, alcohol, aspirin, sleep deprivation, inflammation, and menstruation. So while you may be safe normally eating a plate of seafood, a glass of accompanying wine could render the dinner party deadly. 

Food-dependent exercise-induced anaphylaxis, where the cofactor of exercise is essential to a reaction, primarily affects men and young adults. Though the prevalence of such a phenomenon is rare and unknown to most people, Professor Pravin Hissaria, a clinical immunologist at Royal Adelaide Hospital, says that he diagnoses the condition approximately once a month. Furthermore, research conducted by Benito-Garcia et al. in 2007 revealed that a large fraction of sufferers are misdiagnosed.

In order to diagnose this complex condition, Prof Hissaria may employ a double-blind, placebo-controlled food challenge, wherein a patient is either fed the suspect food or another substance, and then instructed to run on a treadmill, to gauge if a reaction occurs. Although this is the ‘gold standard’ of diagnosis, it can be risky; the alternative of skin-prick testing, however, is unfortunately often inaccurate. A blood test to detect antibodies to omega-5-gliadin is useful in wheat-dependent cases. Additionally, Dr Malik stresses that the level of exercise needed to induce a serious reaction is unpredictable and can vary between patients. “For some,” he adds, “[a reaction occurs while] digging, some when rushing to the bus, while others require a cycling marathon.” This greatly complicates the diagnostic process, but also places some patients in grave danger. Dr Malik admits that “some patients think it is made up, and refuse to believe [such a phenomenon of two-factor anaphylaxis] exists,” due to the condition’s great variance. 

To further complicate matters, the enigmatic aetiologies, or causes, of this condition are not fully understood within the immunological community. Doctors think that reactions are triggered by either the increased absorption of alternative food allergens, or reduced blood flow to the gut. The optimal management of the condition is also contentious. Prof Hissaria encourages patients to entirely separate both culprits, advising them to avoid exercise for four to six hours after consuming the responsible food. Conversely, Dr Malik advises completely omitting the food, as mild exertion is often unavoidable, yet for some patients lethal. Research is currently underway regarding the potential preventative use of omalizumab, a biological agent which binds to and blocks allergic antibodies.

A complex condition also garnering attention due to its incredulous nature is tick-induced mammalian meat allergy. Groundbreaking work in the identification of this phenomenon emerged from Sydney, owing to Professor Sheryl van Nunen and her observations in her Chatswood clinical practice. Her research has been so instrumental to the global understanding of the impact of tick bites that she was awarded the 2021 Order of Australia for outstanding service to medicine. 

Prof van Nunen documented that when a tick bites a human, it injects a carbohydrate from its saliva known as alpha-gal. Up to one-half of the patients bitten by a tick make antibodies in response to the foreign antigen, which is also found in four-legged mammals. Just as a vaccine prepares the immune system to react upon re-exposure to the antigen, re-exposure to alpha-gal with meat consumption can trigger a reaction. However, although 50% create antibodies, only 8% of those bitten experience a reaction due to augmenting factors. This condition is particularly pernicious in that an allergy to mammalian meat sometimes induces reactions to milk products, gelatine and medicines that contain animal products. This can preclude sufferers from receiving heart valve prostheses, snake antivenoms and certain vaccines. 

When asked about what led to her discovery, Prof van Nunen revealed that reactions occurred in the “middle of the night”, which is not typical of food-induced allergy. After excluding the more common semen or latex allergies, she realised the delayed absorption of meat from the stomach was the cause. Just as certain international research that shone light on the fugitive ticks in Sydney’s Northern Suburbs “set a fire around the world, like a piece of cordite,” further understanding of these complex conditions will emerge with ongoing research. For now, the one thing that researchers know for certain is how much remains unknown. 

*Name changed to preserve anonymity

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