Cofactors for Allergic Reactions; What Are They and What, if Anything, Can You Do About Them?

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What are cofactors for allergic reactions?

According to the European Academy of Allergy and Clinical Immunology(EAACI), cofactors for allergic reactions are ‘patient-related or external circumstances that are associated with more severe allergic reactions’. That is, anything about you, the things you do or the circumstances you find yourself in that contribute towards making your allergic reactions (mainly to food) worse.

The 3 most commonly reported cofactors are exercise, medications and alcohol.

In 2014, German researchers proposed a more specific terminology, grouping risk factors for anaphylactic reactions into 3 categories:

1. Augmenting factors; things which influence the severity of reaction through immunologic mechanisms, such as exercise, medications (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), antacids), alcohol, body temperature, acute infections and menstruation
2. Concomitant diseases; conditions which are associated with more severe reactions and/or increased mortality, such as asthma, mastocytosis and heart disease
3. Cofactors; things which do not seem to act through immunologic mechanisms—although this is a controversial category that may exist simply because of a lack of evidence—such as age, emotional stress or specific allergens (e.g. peanuts or tree nuts)

However, this classification has not caught on and the term ‘cofactor’ is generally used to describe any factor which could potentially influence the severity of an allergic reaction.

I like to categorise cofactors into things things that you have no real control over:

• Age, sex and race
• Infections
• Immunological disorders (mastocytosis)

Things you do have a degree of control over:

• Medications
• Eczema and asthma
• Stress
• Lack of sleep
• Body temperature

And things you have quite a bit of control over:

• Exercise
• Alcohol
• Food (and its) preparation

It’s good to remember that, even if you don’t have any control over certain things, you do have control over how much you choose to learn about your allergy which, in turn, gives you control over how you deal with it, from avoiding unnecessary risks to learning how to spot the signs and symptoms of reactions and knowing how to deal with them.

Cofactors are thought to worsen reactions in 2 ways:

1. They can lower the threshold of a reaction, meaning that the amount of food needed to trigger symptoms is smaller—ii.e. they make a reaction more likely to happen. In some cases, a person can have no symptoms at all to a normal portion of their trigger food in the absence of a cofactor, but will react the food when a cofactor is present, something that’s now believed to happen in cases of food-dependent exercise-induced anaphylaxis (FDEIA)
2. They can worsen the severity of a reaction—i.e. they make the symptoms worse—such that a person who would otherwise only have mild symptoms after eating a certain amount of food in the absence of a cofactor has a more severe reaction when they eat the same amount of food with a cofactor present

Sometimes the presence of a cofactor can seem to reverse an acquired tolerance to a food; for example, there is the case of 16-year-old girl who had been allergic to milk when she was younger and had proven that she was tolerant to milk during an oral food challenge when she was 14, but then developed FDEIA to milk and had episodes of anaphylaxis after jogging or playing basketball.

What may be happening in cases like this is that the person never completely lost their allergy to their trigger food but now requires large amounts of it to have a reaction—the presence of exercise (and/or another cofactor) simply lowers their threshold so that they react to smaller amounts of it.

How cofactors manage to do this is still being researched, but the various mechanisms they use basically seem to result in 2 things:

1. increased intestinal permeability that allows more food allergens to be absorbed into the bloodstream (i.e. makes the allergens more ‘bioavailable’), and/or
2. decreased activation threshold of immune system cells—notably mast cells and basophils—which require less of an allergen to provoke them into releasing inflammatory mediators like histamine

Anaphylaxis that only happens in the presence of more than one trigger is called ‘summation anaphylaxis’. The best known example of this type of reaction is food-dependent exercise-induced anaphylaxis, defined by the fact that a person can either eat their food trigger or exercise without problems, but when they do a combination of both, they have a reaction that is often anaphylaxis.

Summation anaphylaxis may well be behind a lot of cases of so-called ‘idiopathic anaphylaxis’, which is what doctors call anaphylaxis to an unknown cause because it sounds snappier than ‘I clearly see signs of a reaction but I have no clue what triggered it’.

Quite often, the presence of more than one cofactor and/or food allergen is needed to provoke a severe reaction. A German study of 93 food- allergic adults managed to identify the triggers for 44 of them. Just over a third (15) only reacted to their food trigger in the presence of a cofactor (or two), and 2 thirds of that group (10) needed more than one cofactor and/or more than one food allergen to provoke a reaction. Food additives, exercise, medication and alcohol were the most common cofactors and wheat, celery, fish, shellfish and hazelnuts the most common trigger foods.

Sometimes one cofactor can be substituted for another, as in the case of a 30-year-old woman who could eat her food triggers and then exercise without any problems, but if she also took some Ibuprofen or she happened to be menstruating, she suffered symptoms ranging from rashes and swelling to anaphylaxis.

Allergists have wondered for a long time why the same person can experience a mild reaction to a food trigger on one occasion and then experience a more severe reaction another time to the same amount of the same food—the presence of one or more cofactors is a possible answer.

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How often are cofactors involved in allergic reactions?

Cofactors reportedly play a role in around 30% of severe reactions to food in adults vs 14% to 18% in children, although numbers vary depending on the population being studied.

A 2017 review of patients of all ages admitted to a Danish hospital with anaphylaxis during the course of a year reported that 58% of the cases were thought to involve cofactors. A 2012 study of 74 Spanish adults with suspected cofactor-enhanced reactions to food reported that 85.1% had suffered from anaphylaxis.

But in populations of food allergic people who do not normally suffer from severe reactions, the numbers affected by cofactors may be smaller. A 2016 study of 496 Dutch food-allergic people older than 16 revealed that only 13% reported more severe reactions to food after the involvement of 1 or more of the following cofactors: physical exercise (10%), alcohol consumption (5%) and use of painkillers (0.6%).

That said, almost two thirds (65%) of those surveyed were unable to say whether any of those cofactors had been associated with their allergic symptoms to food. And if your food allergy is not that serious, you’re unlikely to look for or spot a connection between potential cofactors and your reactions to food, and there probably won’t be much of an investigation into them. This study also only looked at 3 possible types of cofactor.

Although exercise, drugs and alcohol are the most commonly reported cofactors, there are many other things that can worsen allergic reactions to food, and the cofactors that affect a child are not necessarily the same as those that will affect an adult.

A review of 1,156 anaphylaxis cases registered in Germany, Switzerland and Austria over the course of almost 3 years found that cofactors were suspected in 39% of the cases involving adults and 14% of the cases involving children and adolescents. In children, the most frequently reported cofactor was physical exercise followed by drugs then infection. In adults, the most frequently mentioned cofactor was medication, followed by alcohol, physical activity and stress.

Other cofactors that are regularly reported in adolescents and adults include sleep deprivation, hormones (namely, oestrogen and the associated menstrual cycle) and concomitant diseases (other illnesses that exist at the same time) like asthma and heart disease.

The fact that children and adults tend to be more commonly affect by different cofactors is probably not because the cofactors function differently in adults and children, but rather because of lifestyle differences.

In fact, lifestyle differences also mean that the most common cofactors are not the same the world over. In Germany, for example, the most common cofactors reported among adults are infection, mental stress, exercise then alcohol. In Korea, physical exercise is apparently the most common cofactor among adults. Children are most likely to be affected by infections, physical exercise and a ‘major change in lifecycle such as travel’. Extreme temperatures, vaccination and ‘excessive physical activity’ are also reported as being problematic for both adults and children.

Ultimately, everyone has their own, individual way of experiencing allergies, and the cofactors that are relevant for one person will be different to those that are relevant for someone else.

You should suspect the involvement of cofactors in your reactions to food if you’ve had intermittent reactions to a certain food despite eating it regularly, or have had episodes of severe reactions after eating (botanically) unrelated foods, or you have a history of reactions to a certain food but have had a negative food challenge.

People undergoing immunotherapy are also particularly susceptible to the effects of cofactors like infection, physical exercise or menstruation, which is why guidelines for this type of therapy generally include the strict monitoring of patients at times when they might be particularly vulnerable and may involve temporarily stopping or decreasing allergen doses.

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Age, sex & race

Age is a well-known factor when it comes to the severity of reactions to food, but perhaps not in the way you think. Although young children are more likely to experience anaphylaxis to food than older children and adults, they are actually less likely to suffer from severe anaphylaxis. This may sound oxymoronic, but anaphylaxis comes in different grades of severity; the basic definition is the involvement of 2 body systems (e.g. serious hives and stomach cramps which involve the skin and gastrointestinal systems), and there are 3 or 4 different grades of anaphylaxis (depending on the definition you’re using). Only the last stage is life-threatening, and that’s the one most people think of when they think of anaphylaxis.

So, although some children do suffer from severe food anaphylaxis, it’s very rare. When fatalities do happen, often either to (pea)nuts or milk, there tend to be a lot of stories about them in the media, which probably helps to fuel the misconception that children are at a higher risk of a deadly reaction to food than they actually are.

The age groups that are thought to be most at risk of severe or fatal reactions to food are teenagers and young adults, something that is often put down to ‘risk taking behaviours’ such as eating foods that ‘may contain traces of’ the food trigger or not carrying their auto-injector.

This, however, may be a misconception. Although there’s probably a grain of truth to the accusations of youthful recklessness, risk-taking is really more a question of character and less a question of age, and accusations of not having or using an auto-injector when you should can be levelled at people in all age groups. Instead, as authors of one study noted, there could be ‘a specific vulnerability to severe outcomes from food-induced allergic reactions’ in that age group.

Analyses of symptoms experienced during oral food challenges have found that older children tend to have lower thresholds and are 3 times more likely to have anaphylaxis than younger children and that they are more likely to need adrenaline to treat their reactions.

For their part, adults are less likely to have anaphylaxis to food than to other types of allergen, namely drugs and venom, but when they do, they’re more likely to experience severe reactions than younger adults and children. The older a person gets, the more likely their reactions are to be complicated by aggravating factors like heart disease and the medications needed to treat those conditions, and the more likely they are to need medical help.

Sex also seems to be a factor that influences reaction severity; in general, although boys are more likely to experience anaphylaxis than girls, women are more likely to experience anaphylaxis after puberty, although men are possible more likely to experience severe reactions (that the research provides mixed results on that point).

The menstrual cycle has been linked to allergic reactions inadolescents and women, either by itself, something which is known as cyclic or catamenial anaphylaxis, or to food in combination with other cofactors such as exercise.

The menstrual cycle has also been linked to more severe asthmatic symptoms, and lots of asthmatic women seem to notice that their symptoms before their period, which could also theoretically aggravate their reactions to food (see later).

Race has also been proposed as a factor that may increase the likelihood of having worse reactions to food. Most of the evidence for this assertion comes from America, where studies have found that African Americans are more likely to be sensitised to a food than any other ethnicity, to self-report a food allergy, to have food-associated anaphylactic symptoms and to die from food-induced anaphylaxis. They are also more likely to have other immunological conditions like asthma which could enhance their allergic reactions.

The American Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) revealed that the largest driver of these differences was shellfish allergy and shrimp allergy in particular.

Their observation is supported by research finding that both children and adults of ‘non-White races/ethnicity’ are more likely to be allergic to shellfish than their white counterparts and that black crustacean-allergic adults are also likely to have more severe reactions.

According to SAPPHIRE, the only foods that are more of a bother to white Americans than to black Americans are posh fruits like avocado and papaya, and gluten. The report also mentions ‘that socio-environmental determinants may play a role in these disparities’.

One of these ‘socio-environmental determinants’ may be where many black people live; a team of researchers on the Food allergy management & Outcomes Related to White and African American Racial Differences (FORWARD) project has noted that black children are more likely than white children to be sensitised to cockroach and house dust mite (both of which are highly-cross reactive with shellfish) and are more likely to have asthma and shellfish allergy. They note that research showing that people who live in inner city areas are more likely to be sensitised to cockroach might explain the link between being African American and being more likely to have an allergy to shellfish.

However, some American research has found that people living in households with different incomes have an equal chance of becoming allergic to shellfish, suggesting that race could be a stronger factor than socioeconomic status when it comes to developing a food allergy.

Outside of the US, the Australian HealthNuts study has reported that infants with at least one parent born in Asia are at an increased risk of an allergy to egg, milk and/or peanuts.

In the UK, a study screening participants for the Learning Early About Peanut Allergy (LEAP) project that found that black children were more atopic—they made more total IgE, egg white–specific IgE and peanut-specific IgE—in their first year of life than white children.

An analysis of emergency department data from three hospitals in Birmingham has reported a higher rate of severe anaphylaxis in British children from families of South Asian descent (Indian, Pakistani and Bangladeshi) than in those from families of European descent, and has noted that this difference has nothing to do with socioeconomic deprivation.

And an analysis of UK Fatal Anaphylaxis Registry data has also reported ‘a remarkable excess of boys with milk allergy with one or both parents from Africa, the Middle-East, or Far-East’, although researchers could not say whether the cause is genetic or cultural.

The fact is, allergy, like life, is messy, and the reasons for the higher risk among these population groups are probably a mixture of both genetic disposition and environmental causes. An interesting study carried out by a team of American researchers tried to untangle these factors as possible causes of allergy. The researchers looked at the data of 601 women enrolled in another population-based study whose self-reported race was either African American or white and examined the relationship between their allergic sensitisation to at least 1 of 7 aeroallergens, their self-reported race and their genetic ancestry.

Although they found that where the women lived was a more important predictor of sensitisation to these allergens than their genetic ancestry, their self-reported race was a strong predictor of their allergic sensitisation even when taking a raft of variables—including where they lived, their income and level of education—into account, which implies that there are other important, as yet unknown, social and environmental factors that influence allergy.

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Infections and immunological disorders

Allergic reactions to food can be influenced by the presence of illness and other diseases, aka ‘comorbidities’. Although this section focuses on infections and allergic disorders, other underlying problems like cardiovascular and thyroid disease also put a person’s body under strain and negatively impact on its ability to deal with allergic reactions (and the emergency medication that may be needed to treat them).

Infections

Clinical experience has shown that infections, especially during the early phases, may make allergic reactions worse. A 2023 review of severe reactions in 774 Turkish patients reported that 148 (19%) had had a high fever prior to experiencing anaphylaxis. Infections are thought to act as cofactors in between 2.5 to 3% of anaphylactic reactions in children and in 1.3–11% in adults.

However, infections are not necessarily believed to influence the severity or occurrence of reactions in people who have milder forms of allergy and they are not always considered significant in analyses of severe reactions, either.

The best evidence for the possible role of infections as cofactors in anaphylaxis comes from anaphylaxis registries, like this analysis of 1962 severe reactions in European children registered between 2007 and 2018 which revealed that ‘acute illness’ was the second most frequent cofactor in anaphylaxis, involved in 14% of peanut-induced reactions and 13% of reactions to other food.

But it’s data from immunotherapy studies involving venom or food allergens that have highlighted the fact that some people seem to experience a fall in the threshold of allergen they can handle if they are unwell with viral infections.

As a consequence, guidelines for immunotherapy advise doctors to delay increasing the allergen intake (up-dosing) when patients come down with an illness during their treatment or to temporarily decrease the dose that patients are being given during their build-up phase.

The underlying mechanisms of how infections may work to worsen reactions are still not understood and may take a while to figure out because, unlike other cofactors, it’s neither ethical nor practical to carry out food challenges with and without infection as a cofactor in human subjects.

Current theories include the possibility that bacterial or viral products can be sensed by receptors on immune system cells—mast cells and basophils—and, under certain conditions, can trigger or enhance their degranulation. Or it could be that a fever and the accompanying increase in blood circulation produces an influx of allergens for the immune system to react to. Gastrointestinal infections may also lead to larger undigested food proteins passing through the inflamed mucosa and reacting with the immune system.

Ironically, the medications that we use to alleviate the symptoms of infection are also recognised cofactors that increase our risk of suffering more severe allergic reactions (see later).

Asthma

Asthma has been mentioned as a risk factor for worse allergic reactions, notably to food and mostly in children, in multiple studies.

In the UK, Ireland and Spain, for example, analyses of hospital admissions have singled out asthma as a significant risk factor for severe reactions. In Sweden, an analysis of the records of children attending the emergency departments of 3 hospitals noted that asthmatic children experiencing anaphylaxis were more likely to have symptoms involving the lower airways (i.e. the lungs) such as wheezing and, in Italy, an analysis of the records of anaphylactic children attending outpatient allergy clinics throughout the country noted that a history of asthma also increased the risk of respiratory arrest.

Meanwhile, in the US, similar research has shown that patients with asthma are more likely to have serious reactions during oral food challenges than those without asthma and 5.2 times more likely to suffer from anaphylactic shock.

People with asthma are more likely to have biphasic—reactions with two phases—or refractory—reactions that persist—possibly because the organs of people with chronic asthma are less able to deal with physical emergencies—they have less ‘physiological reserve’—and/or their bodies are dealing with more active inflammatory processes that are further aggravated during anaphylaxis.

Asthmatic children who have anaphylactic attacks are more likely to receive multiple doses of adrenaline than children without asthma, that asthmatic children who are admitted to hospital are more likely to have low blood pressure and to be intubated than non-asthmatic children, and that anaphylactic patients with asthma are more likely be placed on a ventilator than those without the condition.

Case series of fatal or near‐fatal anaphylactic reactions to food also commonly report that the people involved have a history of asthma as well as food allergy. In the UK, an analysis of fatal and near‐fatal anaphylactic reactions in people admitted to hospital between 1992 and 2012 reported that 97 of 124 (78%) fatal cases were patients diagnosed with asthma. In the US, a similar analysis found that 24 of 25 (96%) subjects for whom there was complete data had asthma. In Australia, that number was 15 out of 22 (68%).

In Canada, only 28% of those who died were reported to have asthma, a relatively low number because in almost three quarters of the cases, asthma status was not reported, but that was still almost 3 times higher than the proportion of people diagnosed with asthma in the general population.

In fact, most fatal food-induced reactions involve difficulty breathing that leads to respiratory arrest (i.e. no longer being able to breathe) which, in turn, causes cardiovascular compromise (i.e. affects the heart’s ability to pump enough blood to the rest of the body).

This all seems to make sense, because when someone is struggling through a life-threatening reaction to food, they often have breathing problems, so an underlying respiratory disease could be expected to make things worse.

In fact, a lot of people with food allergy and no formal diagnosis of asthma have also been reported to have hyperreactive lungs, which also predisposes them to having more serious allergic reactions. And lung diseases like chronic obstructive pulmonary disease have also been shown to predispose any food-allergic person to having more severe reactions.

Additionally, a known history of breathing problems can also make it more difficult to recognise—and therefore treat—an anaphylactic reaction in the first place.

However, the importance of asthma as a cofactor is disputed; a large proportion (generally, over half) of food-allergic children have asthma, yet the vast majority of food-allergic people with asthma (>99.9%) will never experience a life-threatening food-allergic reaction—in fact, Europeans in general are more likely to be murdered than to die from an allergic reaction to food. Therefore, asthma is therefore, in itself, not a good predictor for severe anaphylaxis.

And some studies have found no link between active asthma and a lower threshold for food allergens, or the severity of reactions during a food challenge, or the severity of accidental reactions or whether or not someone will successfully complete a course of oral immunotherapy. Some research even finds that children with asthma (and eczema) are less likely to suffer from severe anaphylaxis than those without co-existing allergies.

It could be that the severity of the condition is key; there is some research reporting that people with severe asthma run a greater risk of experiencing anaphylaxis and life-threatening reactions than people with milder forms of the condition.

Unfortunately, most of the studies on the subject do not assess the importance of asthma severity, (and those that do don’t report particularly convincing numbers, such as this survey of members of the UK Anaphylaxis Campaign, which reported that 41% of those who’d had anaphylaxis had asthma that they categorised as severe) meaning that the evidence trying to link severe asthma to more serious reactions is not as strong as it should be.

It could be that poor asthma control is the most important factor. However, although there is some research that suggests that asthma exacerbation might be associated with severe or fatal reactions to food, most medical records do not enable analysts to judge whether or not this is the case, and there is some research that finds no link between poorly controlled asthma or exacerbated symptoms and more severe or fatal reactions.

In the end, the data assessing asthma as a risk factor are inconsistent and have been described as ‘contradictory, even within the same dataset when severity is assessed using different criteria.’

So the jury remains out on the subject of asthma as a genuine cofactor for more severe reactions, but the evidence gathered so far suggests that it would still be wise to take extra care with your trigger food(s) if you feel unwell, and the more you do to keep your respiratory illness under control, the milder your allergic reactions are likely to be.

This line in caution is also followed by allergists all over the world who exclude people with poorly controlled asthma from doing food challenges or from allergen immunotherapy.

Eczema

Allergic eczema—aka atopic dermatitis—is also sometimes mentioned as a possible cofactor for worsening reactions. For example, a case-control study of allergic Brits with and without asthma found that eczema was associated with a significantly increased risk of anaphylaxis within both groups. Another study of Canadian fruit-allergic children and adults admitted to hospital with anaphylaxis reported that severe reactions were more likely to occur among those with eczema.

However, most studies that have looked into the impact of eczema on allergic reactions have found no association between having the skin disease and having more severe reactions. On the contrary, some studies have even found that children with atopic dermatitis actually have a lower risk of suffering severe reactions to food than children who don’t have the condition at all.

So, although children with eczema may have a bigger chance of having an allergy to the most common childhood food allergens, especially egg, and are well represented among may be well represented among registered cases of anaphylaxis there is little evidence to suggest that merely having eczema puts you at greater danger of suffering from severe allergic reactions.

As it is with asthma, the key may be the severity of the condition and whether or not it’s under control. For example, a case series of British patients with nut allergy found that severe eczema was linked to a 3-fold risk of becoming unconscious during an anaphylactic reaction and an analysis of the UK’s Fatal Anaphylaxis Registry noted cases of fatal reactions that were associated with eczema flare-ups. Again, it would be wise to take extra care with your trigger food(s) if you feel unwell.

Mastocytosis

Mastocytosis has been linked to a higher risk of severe anaphylaxis, which makes sense, given that it’s a condition characterised by the production of abnormally high numbers of mast cells in the body which have the potential to release large amounts of histamine into the blood.

There are 2 types of mastocytosis:

• cutaneous mastocytosis, where mast cells gather mainly in the skin and which mainly affects children
• systemic mastocytosis, where mast cells gather in the skin, internal organs and bones and which mainly affects adults

Systemic mastocytosis is the condition that is linked with more severe allergic reactions, and mastocytosis as a cofactor is therefore primarily a problem affecting adults, although children can be affected, too, especially when they have extensive skin disease. (2)

The evidence for a link between mastocytosis and a higher risk of anaphylactic reactions to hymenoptera (sawflies, wasps, bees, and ants) venom, is especially strong, with research reporting that men with the condition are at greater risk than women, and that severe reactions are likely to occur when a person is stung again.

There are also case reports describing severe reactions to insects from other families (namely to Hippobosca equina from the Hippoboscidae family) and a rare fatality after a yellow jacket sting.

However, there is no clear link between mastocytosis and food-induced reactions. This does not mean that people with mastocytosis do not have severe reactions to food, but that mastocytosis is often not an aggravating factors in those cases—something else like medications may be instead. That said, as ever, there are always a few exceptions to prove the rule, although those with the condition who do react to food may need more than one trigger to set them off. No severe, let alone fatal, reactions in food-allergic people with mastocytosis have yet been reported.

People with mastocytosis, especially children, can regularly be involved in episodes of anaphylaxis without a clear cause—so-called ‘idiopathic anaphylaxis’—so systemic mastocytosis should be considered in someone who has had a severe reaction to an unknown trigger.

In the lab, elevated levels of tryptase—the major protein component found in mast cells—in the blood are sometimes used as a marker for mast cell activation. Studies examining tryptase levels in people with venom allergy and histories of severe reactions have linked relatively high circulating levels of the protein with a greater chance of suffering from severe allergic reactions and have suggested that people with high levels of tryptase and histories of systemic reactions to Hymenoptera stings should be examined for possible mast cell disorders.

Mastocytosis is not the only condition that can be associated with high circulating levels of tryptase, a genetic condition called ‘hereditary alpha tryptasaemia’ (HαT) which affects around 5% of the general population also results in high levels of tryptase in the blood and has also been linked to more severe reactions to hymenoptera venom.

In contrast, a clear link between elevated levels of tryptase and more severe reactions to food has not been clearly demonstrated, even though some studies have suggested that tryptase measurements could be used to predict the risk of anaphylaxis in children with food allergy in general and milk allergy in particular, and has also been mentioned as a possible marker for symptom severity in adults.

However, individual differences in baseline levels of tryptase make it difficult to come up with general cutoff points that will apply to most people (just as it is with the standard IgE measurements, to be fair). Some studies report that even slightly raised levels of tryptase in the blood can lead to severe reactions, while others find that tryptase levels are can be quite high during milder reactions to food and are often not increased during severe or even fatal reactions.

All in all, raised tryptase levels are probably more useful in diagnosing (potential) anaphylaxis to medications, unknown triggers and venom.

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Pollen season

Research suggests that simply having hay fever is not necessarily a risk factor for having more severe allergic reactions. For example, an analysis of the records of anaphylactic Italian children attending outpatient allergy clinics found no link between a history of hay fever and having severe reactions to food, and an analysis of the medical records of patients receiving anaphylaxis treatment in US emergency departments actually noted that people with severe reactions were less likely to have hay fever.

Similarly, a study examining the characteristics of Dutch children undergoing food challenges found no link between having hay fever and severe reactions, and another study of Norwegian children undergoing oral immunotherapy for peanut allergies reported that those with hay fever were no less likely to discontinue treatment (in fact, twice as many children with hay fever successfully completed the treatment than failed to get through it).

That said, some research, notably in people allergic to (pea)nuts, has reported a link between having severe hay fever and severe symptoms of the upper airways (nose and throat), including a 3.8 fold increased risk of having a severely swollen throat (pharyngeal oedema)

Additionally, a review of 1,156 anaphylaxis cases registered in Germany, Switzerland and Austria reported that a third of the children had hay fever, as did half of the adults. In fact, hay fever was the most common accompanying disease in anaphylactic adults, which makes sense because it seems to takes time to build up environmental allergies and adults are more likely to have seasonal allergies than children.

The key factor as to whether your hay fever may provoke a more dangerous allergic reaction is probably the time of the year. Multiple studies suggest that food-allergic people with hay fever are at greater risk of suffering worse reactions during their relevant pollen season.

Studies from Sweden, Denmark, Italy and Japan that have investigated the symptoms in people allergic to food and pollen have reported that many of them suffered more (severe) symptoms to plant foods during pollen season, as has one study that looked at yet-undiagnosed adults in the general population.

Similarly, studies that have looked at hospital admissions for anaphylaxis in Britain, Sweden and Canada have all reported more admissions for plant food-induced anaphylactic reactions in adults and children during (tree) pollen season.

Some doctors have also noticed a tendency for patients with hay fever to be more likely to experience reactions to their immunotherapy doses during the relevant pollen season, even when they have tolerated those doses before, and a 2021 study reported a case of anaphylaxis during grass pollen season in a patient with grass allergy undergoing treatment for peanut allergy, which was particularly notable as reactions to grass pollen itself are typically quite mild.

Reactions may become worse towards the end of pollen season. Many decades ago, researchers established the existence of something they called a ‘priming effect’ which describes the tendency of a pollen-allergic person’s airways to become gradually more and more irritable and ready to react (to both the airborne irritants they are allergic and those they are not) as the pollen season goes on. Towards the end of the season, they tend to experience a greater allergic reaction (to smaller doses of allergens) than they did at the start.

This phenomenon is at least partly caused by the fact that these ‘primed’ immune system cells produce more inflammatory mediators like histamine as the pollen season goes on and they become increasingly irritated, and it’s this increase in immune cell sensitivity and activity that may cause more severe reactions to food.

Reactions may be even worse when a person is exposed to more than one cofactor, as illustrated by a French case report that describes the experiences of a 13-year-old peanut-allergic girl and a birch-pollen-allergic 18-year-old man who both normally tolerated hazelnuts but had anaphylactic reactions after eating the nuts during their individual pollen seasons. Both of these patients were experiencing problems with other cofactors at the time of their reaction: the girl was suffering from asthma which was uncontrolled when she experienced anaphylaxis and the man was suffering from intense stress, which brings us neatly to our next category..

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Stress

Stress and its role in allergic reactions has been largely ignored until recently, but research is now highlighting its relevance, finding ‘psychological burden’ to be one of the major risk factors for having severe anaphylactic reactions.

How stress contributes to the development and aggravation of food allergy is, as yet, unclear, and much of the research to date has focused on stressing out animals, namely rats, to try and find answers. However, researchers have also stressed groups of people out in the name of allergological science and have found that, regardless of whether the stress is physical—such as the pain induced by cold—or psychological— such as the pain induced by having to perform difficult mental tasks—similar responses occur in the human body; namely, immune cell activation and a leakier gut.

Before you start frantically scrolling through recommendations for relaxing essential oils or the best recordings of whale song, you may be relieved to know that the kind of stress that could lead to intestinal problems would have to be either intense or chronic.

In fact, this helps to explain why these kinds of experiments have typically produced positive results when carried out using rats—who are generally subjected to acute stress lasting for a couple of hours or chronic stress lasting for a couple of weeks—but inconsistent results when they’re performed in humans who will, at most, have to suffer through 15 minutes of acute stress and cannot be purposefully subjected to chronic stress.

However, these conditions can be found in day to day life, and some studies have taken advantage of this fact; research carried out on people undergoing military combat-training for a period of a few weeks, for example, have reported that those physically and mentally stressful conditions do increase a person’s intestinal permeability (and give them stomach troubles).

Conversely, the kind of stress undergone by someone who goes skydiving does not affect intestinal permeability; in that case, the stress both lasts too short a time and is voluntarily undergone by people who enjoy those kinds of high-adrenaline situations.

Researchers have also used the naturally stressful conditions of students anticipating an oral presentation for their bachelor or master thesis to study a person’s response to chronic stress, and this has produced results both supporting and refuting the idea that chronic stress increases intestinal permeability.

The fact is, it’s difficult to achieve the same kind of stress response in humans that is seen in animal studies, because scientists who want to publish papers in respected journals have to maintain ethical standards, and we also still don’t know what kind of individual factors may affect the results.

We do know that an already damaged gut barrier seems to facilitate the negative effects of stress, with research on patients with inflammatory bowel syndrome (IBS) finding that chronic stress increases inflammation in the gut. Chronic physical and psychological stress also seems to affect women(‘s intestines) more than men(‘s), potentially explaining why more women seem to develop IBS.

Additionally, a separate strand of research has revealed that stress seems to affect the makeup of our gut bacteria which, in turn, may influence whether or not we become allergic to certain foods.

This link between stress and allergy helps to explain the results of studies which have tried psychological interventions to alleviate the symptoms of allergic diseases—such as expressive writing about stressful events, mental imagery and yoga—and have reported encouraging results.

The research on this topic is still in its infancy, but the prospect for people to positively influence their allergies by learning to keep calm while soldiering on seems promising.

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Sleep deprivation

A recent study looking into the effects of cofactors on people with peanut allergy found that a lack of sleep considerably reduced their threshold of reactivity, putting them at greater risk of a reaction.

In the study, patients underwent 3 food challenges with peanuts; one with exercise after eating peanuts, one with a bad night’s sleep before eating peanuts, and one with no intervention. Sleep deprivation reduced the threshold dose of peanuts needed to trigger a reaction by 45% (as did exercise).

The study data also showed that sleep deprivation increased the severity of the symptoms by 48%, whereas exercise had no effect.

A lack of sleep has also been found to reduce the threshold of people undergoing oral immunotherapy for peanut allergy.

Why this happens is unknown, although one theory is that sleep deprivation may stress the gastrointestinal tract and enhance intestinal permeability.

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Body temperature

The human body prefers to work within a relatively narrow temperature range. This is most often noticed when people exercise, which is why there are several reports of people suffering allergic reactions to foodonly when exercising in the cold, or in a warm environment. As with ‘regular’ cases of food-dependent exercise-induced anaphylaxis (FDEIA), these people can eat the foods they are sensitised to without experiencing any reactions as long as they don’t exercise within a few hours of eating and, in their specific cases, stay within a certain temperature range.

Temperature also affects some people who are allergic to exercise itself, as shown by one study which describes a case of familial exercise-induced anaphylaxis (yes, the condition can run in families) that includes a 16-year-old girl who experiences anaphylaxis when she gets hot during exercise, and a report which describes the case of a 16-year-old boy who experiences anaphylaxis when exercising outdoors in the winter.

Exercise and temperature—namely heat and humidity—were also the triggers for a 38-year-old woman who initially started suffering from anaphylactic attacks after doing strenuous exercise. Unfortunately, she lived in Qatar, where it is often hot and humid, especially during the summer, and she later developed severe symptoms after carrying out usual daily activities like walking from the parking lot to her office. Ultimately, she had to be given monthly shots of an anti-IgE medication called omalizumab (brand name Xolair) which enabled her to get on with her life without having any more attacks, including during exercise.

Temperature—namely hot showers—has also been reported to provoke severe allergic reactions in food-allergic people undergoing immunotherapy.

(Some people are allergic to the temperatures themselves—allergy to cold or heat has been recognised relatively recently as a problem for a small number of people who can experience anything from hives through to anaphylaxis when they’re exposed to a change in temperature triggered by a range of things including air temperature, food temperature or stress.)

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Exercise

Physical exercise (regardless of body temperature) is the most common and well-studied cofactor for allergic reactions. It mainly affects reactions to food, alcohol and medications, notably nonsteroidal anti-inflammatory drugs (NSAIDs). It’s thought to be involved in anywhere between two thirds and a tenth of all anaphylactic reactions although there is currently some debate as to how important it actually is.

People allergic to food who are affected by exercise have historically been placed into 2 categories; those whose allergic reactions to food are worsened by exercise and those who only have allergic reactions to food when they exercise. People in the latter group are said to have food-dependent exercise-induced anaphylaxis (FDEIA), a condition that does not necessarily involve food and does not always provoke anaphylaxis. There is also currently a debate over whether or not those 2 categories should be considered separate.

Experts are not sure how exercise actually works to worsen allergic reactions, but they have put forward several theories that involve either making more food allergens available to provoke a reaction (e.g. by making the gut more permeable) or making the immune system more likely to react (e.g. by lowering blood pH and making mast cells more likely to release inflammatory chemicals like histamine). None of the current explanations can satisfactorily explain why some people with FDEIA only need to do the ironing or have a bit of a stroll to provoke a reaction, though.

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Drugs & alcohol

Both medications and alcohol are reported relatively often as cofactors in severe allergic reactions, with both apparently becoming more of a bother as we get older (I say ‘apparently’ because there aren’t any reports of drunk, food-allergic children around to help us know for sure whether it’s an age thing or more of a lifestyle problem, and setting up an experiment to find out would undoubtedly lead to a loss of funding).

Medications seem to have more of an adverse effect on allergic reactions. A study which involved giving 25 adult patients with wheat-dependent, exercise-induced anaphylaxis (WDEIA) gluten challenges with and without various cofactors reported that the threshold for a reaction to wheat was lowered by 83% when a person took aspirin and by 36% when they drank alcohol. Aspirin also increased the severity of the reaction, whereas alcohol did not.

The mechanisms underlying the reactions are not completely understood, but there are 2 main theories:

1. They increase intestinal permeability, leading to an increase of allergen absorption into the bloodstream
2. They activate mast cells and basophils directly, prompting them to release their biochemicals, including histamine

Nonsteroidal, anti-inflammatory drugs (NSAIDs)—including over-the counter medications like aspirin and Ibuprofen—are most commonly mentioned in connection with allergic reactions, often in combination with food and/or exercise. Studies mention their use as possible cofactors in 2% to 22% of reactions involving food.

Medicines that are used to treat cardiovascular disease—namely angiotensin-converting enzyme (ACE) inhibitors and beta-blockers—are also frequently implicated in more severe reactions, linked to about 0.6% to 10.5% of reactions to food and also to more severe reactions involving insect stings.

β-blockers and ACE inhibitors both increase the risk of severe reactions individually, but they are even more of a risk when used in combination. They are thought to work by decreasing the threshold of mast cell activation—i.e., making them more likely to degranulate and release chemicals like histamine. Propranolol (a beta-blocker) is also known to cause increased airways resistance in some people with asthma.

Because this type of medication is often used by older people with underlying problems like cardiovascular disease, it can be difficult to untangle the impact of the medication on the severity of the reaction from the underlying reason for having the prescription in the first place, but a couple of studies that have adjusted for age have noted a linked between ACE inhibitors (but not beta-blockers) and severe anaphylaxis and both ACE inhibitors and beta-blockers and multiple organ system involvement and the need for hospital admission.

Antacids—proton pump inhibitors (PPIs) in particular—are the last category of medications to be regularly mentioned as a risk for more severe reactions to food (about 5% of cofactor-induced reactions).

They are though to worsen reactions because, as they do their jobs and lower the levels of acid in the stomach, they inhibit the proper digestion of food, which enables the allergens to reach the intestine and be absorbed into the bloodstream more or less intact and thus better able to provoke the immune system.

Antacids have been linked to anaphylactic reactions to previously tolerated doses of food during immunotherapy and have also been shown to promote new sensitisations to food in people who use them for a few months.

When antacids are used to protect the stomach and intestinal linings from damage caused by painkillers during long-term pain- or anti-inflammatory therapies (to manage of rheumatoid arthritis, for example), some people can develop allergies to the antacids themselves.

As far as alcohol is concerned, it’s been reported as a cofactor of anaphylaxis in between 1% and 16% of adult food-allergic adults; numbers vary according to the population under study and when the study was carried out. For example, a questionnaire survey of a survey of members of the British anaphylaxis campaign reported it as a factor in 15.2% of reactions, whereas data from one centre in Germany in 2008 reported that it only affected 1% of their patients, while data from the anaphylaxis register of central European countries (Germany, Austria and Switzerland) found that it was involved in 9.6%.

Meanwhile, in a potentially worrying trend in France, alcohol was reported as a factor in 3.7% of reactions in 2002, in 5.9% of reactions in 2003 and finally in 10.1% of reactions in 2007, in a study that also included children. (Just kidding, these numbers just help to illustrate what happens when doctors and patients become more aware of something as a potential problem. And the difficulty in comparing numbers from different population samples).

By contrast, in the sober Netherlands, where the number one cofactor seems to be exercise, a questionnaire study of patients visiting one centre in 2016, reported a that mere 5% of the reported reactions in people over 16 years old were linked with alcohol (and only 0.6% with painkillers). Then again, another survey of Dutch food-allergic adults reported that alcohol consumption may have been a factor in 16% of their accidental allergic reactions to food.

Meanwhile, an analysis of the data of Italian adults with exercise-induced anaphylaxis found that alcohol was more frequently involved in reactions involving men and an analysis of the European anaphylaxis register found that alcohol was especially problematic for people with an allergy to wheat.

There are several existing theories as to how alcohol may work to worsen allergic reactions. Not inconsequentially, it can impact on risk-taking behaviour, potentially making people less likely to avoid allergens and affecting their ability to respond to symptoms.

On a physiological level, research has found that alcohol has inflammatory effects, boosts the concentration of IgE antibodies in the blood, increases gut permeability and may even work to activate mast cells directly.

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Food preparation

It’s not just the food itself—like peanuts, tree nuts, milk or shellfish or, especially when cofactors are involved, wheat—that puts a person at risk of a severe allergic reaction, it’s anything that makes it easier for your body to absorb the food allergens and thus react to them.

One of those things is simply the amount of food you eat. The amount of food that a person can eat without getting symptoms—the threshold dose—varies a lot between individuals, and it would be a mistake to think that people who react to smaller amounts of food are at higher risk of anaphylaxis. One analysis of food challenges carried out in the Netherlands, for instance, found that the eliciting dose only predicted 4.4% of the variation in the reaction severity.

So, although a person with a history of severe reactions to cashew nuts, for example, may react badly to a tiny amount of cashew, research has found that people with histories of severe reactions do not necessarily react to smaller amounts of food than people with a history of milder reactions to that food.

An excellent example of individuals who could be considered relatively ‘insensitive’ to food while still being at risk of severe reactions are those who have food-dependent exercise-induced anaphylaxis; they are typically people who can eat a large amount of their trigger food until they add a cofactor like exercise or aspirin, at which point they will often have an anaphylactic reaction.

For any given person, the absence of prior anaphylaxis could simply be due to the fact that they did not eat enough of their food trigger, rather than them being at an inherently lower risk of a serious reaction.

This was neatly illustrated by a unique study in which food challenges were given to 27 peanut-allergic children and, instead of stopping the challenge at the first sign of a reaction, the children were given larger doses of food until the maximum dosage was reached or they had a severe reaction. Ultimately, anaphylaxis was provoked in 21 of the children. Only 3 children had anaphylaxis as soon as they reached their eliciting dose. In almost 2 thirds (62%) of the cases, the first reactions were mild, but they got progressively worse the more peanut the child ate.

Another thing that can affect the severity of allergic reactions is food processing. Heating, for example, can destroy the 3D structure of certain food proteins to such an extent that they are not able to bind as well to IgE antibodies as they used to, thereby reducing the severity of allergic reactions.

The effect of heat on various types of food allergen is unpredictable; heating tiger prawns, for example, can make them more allergenic, whereas heating tropical oysters will make them less likely to provoke a reaction.

Neither does a food allergen respond to different types of heating in the same way; roasting peanuts, for example, makes them more allergenic, whereas boiling them reduces their ability to provoke reactions.

The effect of processing on foods is complex and a lot of research remains to be done before we have a good overview of the subject, but baked eggs and milk in particular have been getting a lot of attention in recent years because they seem to be tolerated by a lot of otherwise egg- and/or milk-allergic people. Cooking these two foods may even allow young children to outgrow their allergies to egg and milk faster, hence the creation of egg ladders and milk ladders by doctors in several different countries.

A favourite vehicle for delivering baked eggs and milk to the allergic are muffins, partly because of the ‘matrix effect’, which is the term used to describe the fact that incorporating, in this case, eggs and milk into a matrix with wheat seems to make some of their allergens even less likely to bind with IgE antibodies and provoke allergic reactions.

Similarly, incorporating peanut, but not egg, into a high fat matrix also seems to inhibit the ability of some of its allergens to bind with IgE antibodies, thus raising the thresholds of people who are allergic to peanuts.

Depending on what type of food allergy you have, these tricks and others—such as peeling your fruit if you have Pollen Food Syndrome—may help you to alleviate your symptoms.

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The bottom line

People with known food allergies and comorbities like asthma are relatively likely to have more allergic reactions during their lifetimes, but the severity of a previous reaction cannot be used to predict the severity of the next one. This may well be because of the presence of cofactors.

The fact is, people who are vulnerable to cofactors are more likely to be surprised by an allergic reaction than people who just react to specific triggers.

In one study of 74 adults with suspected cofactor-enhanced food allergies, 85% of the reactions were classified as anaphylaxis. Interestingly, about two thirds of the adults reported that they normally tolerated their trigger food. Some reported mild oral allergy syndrome (OAS) when they ate their trigger food, which didn’t stop them from eating it regularly. When some of the adults who had reacted to foods they didn’t eat regularly were given food challenges, they either tolerated the food or had OAS. However, the involvement of cofactors like medication, exercise or alcohol suddenly made their reactions much worse.

For this reason, some scientists are warning that the food challenges carried out in labs which are used as guidance for voluntary trace allergen labelling may be overestimating the amounts that people can eat, because these tests take place in ‘sterile’ controlled settings and do not (really, cannot) take the cofactors that affect many of us every day into account.

Allergic reactions are very personal and trying to determine what your cofactors are is not easy. Not only do some of us require an unexpected mix of factors to trigger our reactions, some people’s vulnerabilities are invisible. For example, some people are less able to metabolise the inflammatory mediators produced during allergic reactions, like platelet-activating factor, which may be linked to a bigger risk of suffering severe anaphylaxis. Only a technician in a lab coat with the right equipment is going to figure that out.

Of course, not all cofactor-enhanced reactions are severe. Some people may not even notice that they have a food allergy until their threshold is lowered by a cofactor and they suddenly have hives, for example.

Personally, my awareness of my food allergy started with 4 seemingly random anaphylactic attacks that came out of nowhere. It took a few years before I finally figured out that the reactions only happened in combination with certain things, and I only managed to do this by keeping records of what I was eating and drinking and when, what I was doing around mealtimes, and what my symptoms were. As I learned more about allergies and found out about cofactors, I learned what to look out for.

In the end, the more you know about what triggers your allergic reactions, the better you’ll be able to manage your allergy. Although it can be difficult to figure out what your cofactors are, simply knowing what to look out for is a great first step in the right direction.Image by Talha Ahmed on Pexels

Image by Talha Ahmed on Pexels