Idiopathic anaphylaxis

Anaphylaxis (pronounced ana-fill-ax-is) is a severe and potentially life-threatening allergic reaction. The common causes of anaphylaxis include food, insect stings, latex and medicines, but sometimes there may be no obvious trigger for the reaction.

If after medical testing and investigation the cause of the reaction is not found, the reaction is then labelled as ‘idiopathic anaphylaxis’ (which means ‘cause unknown’). This does not necessarily mean the reaction took place without something triggering it; it simply means that no trigger can be identified.

Sometimes it could mean there is an unusual external trigger, such as a rare food allergen for which there is no skin or blood test, or which tests fail to pick up. Sometimes it means there is no external trigger; instead, the cause is a temporary increase in the reactivity of the immune system. This increased reactivity usually clears up within a few weeks or months, although in some cases the condition may take a year or two to settle. A key message in all cases is to visit your GP and ask for a referral to an allergy clinic.

It is important to see your GP as soon as possible if you suffer any symptoms that you think may be caused by an allergy. Even mild cases need to be medically assessed because the next reaction, in some cases but not all, could be more severe.

Some GPs have a clear understanding of allergies and similar conditions, but it’s more likely your doctor will need to refer you to an allergy clinic. Guidance issued by the National Institute of Health and Care Excellence (NICE) recommends that following emergency treatment for suspected anaphylaxis, people should be offered referral to a specialist allergy service (NICE clinical guideline 134, 2011). Your GP can locate an allergy clinic in your area by visiting the website of the British Society for Allergy and Clinical Immunology (www.bsaci.org).

Once you get a referral, the consultant will discuss your symptoms with you in detail as well as your medical history. The results of skin prick tests and blood tests may help the specialist identify the cause of the problem. If no cause can be found, then the term idiopathic anaphylaxis is used. Sometimes the cause of the first attack may not be obvious but the trigger can become clearer if you experience further attacks.

Food should be considered as a prime suspect. Foods eaten a few minutes before the start of an attack are the most likely culprits. While it is less likely when food was eaten more than an hour before the start of an attack, there are some rare causes where there is a longer delay such as with red-meat allergy (see below; Delayed allergy to red meat).

The most common food triggers are shellfish, fish, peanuts, tree nuts (such as cashews, walnuts or Brazils), milk, eggs and wheat, although many other foods have been known to trigger anaphylaxis. If a particular food is suspected, but skin or blood tests are unexpectedly negative, the consultant may suggest an oral food challenge test to remove this food from the investigation. This is where you eat a very small amount of the suspect food while under medical observation, gradually building up the amount eaten until symptoms occur or it is shown that the food is not the cause of the reaction. This should never be performed at home. There are also situations where a food allergy only causes a reaction if followed by intense exercising (see below; Food plus exercise).

Prescribed drugs, insect stings and latex may also be considered as the cause of the reaction. Any medication taken for years may suddenly cause anaphylaxis. If skin tests are not available for a suspected medication, you may be required to stop taking it for a short time and then take a test dose. This must be done under supervision in hospital.

A diagnosis of idiopathic anaphylaxis should only be made after an extensive medical investigation. This should include a review of all hospitalisation and A&E records.

When someone suffers a suspected allergic reaction, they may be tempted to consider one of the common food allergens as the culprit, such as peanut or shellfish. Indeed, this may prove to be the case, either because the allergen was present in the food eaten or because of cross-contamination somewhere in the food production process. However, the cause of the problem may be less obvious. A few possibilities are presented here.

• Lupin: The seeds from some varieties of lupin are milled to make flour, which is used in baked goods such as pastries, pies, pancakes and in pasta. Allergy to lupin has been recognised for some time in mainland Europe, where lupin flour is used fairly commonly in food products. In the UK, cases of lupin allergy are less common because lupin is rarely used in foods. If you suffer an allergic reaction and discover that lupin was present in a food you have eaten, you might consider this as the possible trigger. By law, lupin must be declared in the ingredients list when present in pre-packed food.
• Buckwheat: Buckwheat use is relatively uncommon in the UK and as a result allergy to buckwheat is rare, but can be missed. Buckwheat does not have to be highlighted as an allergen in ingredient lists by UK law. Despite its name, buckwheat is unrelated to wheat. Buckwheat is sometimes used in gluten free foods, some savoury pancakes/crepes and Japanese noodles.
• Natural Rubber Latex (NRL): This is found in thousands of everyday products. Reports of allergy to Natural Rubber Latex have become increasingly common over the past 25 years and severe reactions occur quite frequently. Many people associate allergy primarily with food – but latex should be considered as a possible cause if a reaction occurs during an operation, during a medical or dental procedure, or just after handling an item made of soft rubber. Some adhesives used in food packaging contain latex (often known as cold-seal, for example in wrappers around chocolate bars), which may cause confusion in identifying the cause.
• Flour contaminated by mites: In 2009 the World Allergy Organisation (WAO) published information on allergy to wheat flour contaminated with mites. The condition is known colloquially as Pancake Syndrome; the medical term is Oral Mite Anaphylaxis. According to the WAO paper (Sánchez-Borges et al, 2009), Oral Mite Anaphylaxis occurs shortly after the intake of foods made with mite-contaminated wheat flour. The condition is seen most frequently in tropical or subtropical environments, but cases are occasionally seen in the UK. Reactions have been reported when cereals have been stored for extended periods at home and the sufferer may mistakenly believe the cause was wheat allergy.
• The oleosins in sesame: A research team reported that proteins called oleosins, which are major allergens of sesame seeds, accounted for about a third of all cases of sesame allergy among the people they studied. However, because oleosins do not dissolve in water, they cannot be identified by allergy skin or blood tests (Leduc et al 2006). Therefore, an allergy could mistakenly be classed as idiopathic when the true cause is sesame seeds. To address this problem, an oral food challenge test may be used for cases where sesame allergy is suspected but cannot be proved.
• Exercise induced anaphylaxis (EIA): This is an uncommon condition in which anaphylaxis occurs after physical activity. It is potentially serious for people affected and requires expert diagnosis. If you think you suffer from EIA, the best course of action is to ask your GP to refer you to an NHS allergy clinic. EIA can also occur in combination with other factors such as a food (see below; More than one trigger?).
• Cold induced urticaria/anaphylaxis: In rare cases, anaphylaxis can be caused by cold. For example, a nine-year-old girl suffered urticaria (hives all over her body) and lost consciousness while swimming in cold water. She was immediately removed from the water and regained consciousness. In the previous two years she had experienced urticaria many times while swimming in unheated water (Fernando SL, 2009). People who suffer from cold urticaria will develop hives when their skin is chilled by cold rain, cold water or cold weather. If you think you suffer from cold urticaria, you may be at risk of cold anaphylaxis and the best course of action is to ask your GP to refer you to an NHS allergy clinic.
• Delayed allergy to red meat: A surprising and unexpected cause of anaphylaxis was discovered in the USA (Tripathi et al, 2014). An allergen in red meat can lead to anaphylaxis several hours after being eaten if the affected person has been previously sensitised (sensitisation is the process in which someone becomes allergic to something in the first place). The condition was first identified in certain areas of the USA, although cases are now being identified in other countries including the UK, Europe and South Africa. The allergen is called alpha-gal (galactose-α-1,3-galactose), which is a sugar molecule found in most mammals. Sensitisation occurs when someone is bitten by a certain variety of tick (hence the reason why the condition is concentrated in certain geographical areas). It has been proposed that it arises if the tick has recently feasted on the alpha-gal-containing blood of a farm animal, however, this may not be the case as alpha-gal is present in laboratory bred ticks.
• Polyethylene Glycol (PEG) allergy: PEG, also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is used in some medications, household products, cosmetics and processed foods. A recent study showed biphasic reactions can occur with PEG allergy, with the first symptoms occuring shortly after exposure followed by a second reaction several hours later (Cox et al, 2021). PEG is found in the Pfizer BioNTech and the Moderna covid-19 vaccines. Chapter 14a of the Green Book states: “The Pfizer BioNTech and Moderna mRNA vaccines contain polyethylene glycol (PEG). PEGs (also known as macrogols) are a group of known allergens commonly found in medicines, many household products and cosmetics. Medicines containing PEG include some tablets, laxatives, depot steroid injections, and some bowel preparations used for colonoscopy.” Individuals with a history of idiopathic anaphylaxis should seek the advice of an allergy specialist before proceeding with vaccination.

• Angioedema: In angioedema, there are recurring episodes of painless swelling that may involve the lips, face (especially around the eyes) tongue, upper airway or anywhere in the body. In many cases no cause for these symptoms can be identified and the attacks stop happening after a few weeks or months. When attacks are persistent, the most common identifiable cause is a side-effect of ACE inhibitors, which are prescribed to treat blood pressure problems. According to research, this treatment sometimes causes angioedema in about 1 person in 300 who takes it (Makani et al, 2012). As the attacks may not start for several months or years after the treatment has begun, this possibility may be overlooked.

Note that although angioedema is a condition in its own right, it can also occur during anaphylaxis and with other conditions such as spontaneous urticaria.

• Hereditary angioedema: is a rare, inherited, non-allergic form of angioedema. In addition to external swelling, there may also be stomach cramps, abdominal pain, nausea and diarrhoea. The episodes may follow localised injury such as dental work. The angioedema (swelling) tends to be painful and slow in onset. This disorder can be differentiated from non-inherited angioedema and anaphylaxis by blood test findings and the lack of other symptoms of anaphylaxis. There are very specific and effective treatments for this condition and therefore accurate diagnosis is vital.
• Spontaneous urticaria: Urticaria (commonly called hives) can occur as part of an allergic reaction, but can also occur when there is no allergy present. Non-allergic urticaria is called spontaneous urticaria and affects 10-20% of people at some point in their lives, and if it persists for more than 6 weeks is known as chronic spontaneous urticaria. Up to 50% of people with spontaneous urticaria, will also have angioedema (swellings) with an attack. However, airway, breathing, circulatory and abdominal symptoms are not features of spontaneous urticaria.
• Histamine poisoning: Histamine can sometimes be present in spoiled fish (especially tuna and mackerel) and can cause similar symptoms to allergy called scombroid poisoning. Unlike an allergy, this usually affects everyone who has eaten the offending food, although some people might be more susceptible than others.
• Mastocytosis: This is a rare condition caused by too many ‘mast cells’ gathering in the tissues of the body. These are the cells that release histamine and other chemicals involved in allergic reactions, causing symptoms such as a skin rash, itchy skin and anaphylaxis. The condition is diagnosed by a special blood test, and it is standard medical practice to offer this blood test to any patient who is suffering from unexplained anaphylaxis.