Idiopathic Anaphylaxis: The Facts

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.

This Factsheet aims to answer some of the questions that you and your family might have if
you are diagnosed with idiopathic anaphylaxis. Our aim is to provide information that will
help you understand your allergy and minimise risks.

Symptoms of anaphylaxis

Mild symptoms may include nettle rash (also known as hives or urticaria) anywhere on the
body, or a tingling or itchy feeling in the mouth. There may be lip or face swelling, which is
not serious in itself unless any of the more severe symptoms listed below are also present.

More severe symptoms may include:

• Swelling of the throat, tongue or mouth

• Difficulty breathing
• Severe wheezing
• Severe abdominal pain, nausea and vomiting
• Feeling faint, dizzy or sleepy

In extreme cases there could be a dramatic fall in blood pressure (anaphylactic shock). The
person may become weak and floppy and may have a sense of impending doom. This may
lead to collapse and unconsciousness.

The speed at which life-threatening symptoms occur varies from person to person.
Symptoms may begin suddenly and progress quickly.

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In general, the first episode of idiopathic anaphylaxis tends to be the most frightening
because the person affected has no understanding of what is happening or what to do about
it. After that, they may recognise the initial symptoms and act quickly.

Getting a diagnosis

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.
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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.

Treating symptoms of anaphylaxis

So that you can treat severe symptoms yourself, your doctor is likely to prescribe injectable
adrenaline (also called epinephrine).

The adrenaline auto-injectors prescribed in the UK are EpiPen®, Jext® and Emerade®, which
are designed for self-administration. You should be prescribed and carry two adrenaline
auto-injectors at all times.

After adrenaline is administered, someone must always dial 999 in case the symptoms
return. Guidelines state that you should lie flat with your legs raised (Resuscitation Council
UK, 2008 and BSACI 2017), although this is not recommended if there is breathing difficulty,
when sitting with arms anchored makes it easier. If you feel as though you may be sick, your
head should be turned to one side. If you feel weak or faint, you must lie-down preferably
with legs angled above the head.

You will need to know how and when to use your adrenaline injector, so training should be
given by a medical professional such as your doctor, local practice nurse or pharmacist. You
can also find help on the website relevant to the injector you carry.

• EpiPen®: www.epipen.co.uk
• Jext®: www.jext.co.uk
• Emerade®: www.emerade-bausch.co.uk

Anaphylaxis can progress rapidly and without early warning signs. Watch out for any
combination of the following signs and then act fast:

• Airway: choking, can’t breathe, tongue or throat swelling, can’t speak clearly
• Breathing: unusually wheezy, noisy breathing, shortness of breath
• Circulation: pale or clammy skin, weak or rapid pulse, faintness, passing out

Use your adrenaline injector, even if unsure. Adrenaline is very safe for everyone but those
with underlying heart disease. Even with underlying heart disease, if there are Airway,
Breathing or Circulation symptoms, the risk from untreated anaphylaxis is likely to be higher
than the risk from adrenaline. Some drugs (such as beta-blockers) can interfere with the
action of adrenaline, and these drugs are often avoided in patients who carry adrenaline
auto-injectors.

If you carry antihistamines for any reason (for example, to treat hay-fever or hives) bear in
mind that these cannot be relied upon in cases of anaphylaxis, even if the symptoms are in
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their early stages and apparently mild. Oral antihistamine treatment delivers no measurable
activity within 30 minutes of the dose, and peak activity is not reached for about three hours.
Adrenaline injected into the thigh muscle is the first line of defence in the treatment of
anaphylaxis.

If you suffer from asthma – especially if it is poorly-controlled – it is likely to increase the

severity of an allergic reaction. If you have asthma, go to your GP and request a review of
your asthma to ensure that you are using the most effective treatment.

Some cases of idiopathic anaphylaxis have an internal cause – a temporary increase in the
reactivity of the immune system. Cases in which attacks are occurring frequently may require
a few weeks or months of regular treatment such as a daily oral antihistamine or steroid to
prevent further attacks and help the condition to settle down. Anaphylaxis may occur for up
to two years before finally burning itself out.

We advise people who have experienced anaphylaxis – whether the cause is known or not –
to wear a medical identification bracelet or talisman.

Finally, we believe it is important to let your family, friends or work colleagues know where
you keep your adrenaline injector and what needs to happen in an emergency. In the case of
children, the school will need a written care plan and staff must be trained in the use of the
injector.

A few possible causes

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
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 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
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 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.

More than one trigger?

For a small minority of people, anaphylaxis can occur when a combination of factors is
present together. This makes diagnosis difficult and without a thorough investigation the
symptoms may be classed as idiopathic. Here we give a few examples taken from medical
literature.

• Food plus exercise: This is called food-dependent, exercise induced anaphylaxis

(FDEIA). The symptoms occur when a food is eaten before exercise. Wheat is often
the culprit food, although others including shellfish are sometimes implicated.
Looking at the available evidence, we believe that anyone diagnosed with FDEIA
should avoid physical activity for 12 hours after eating their trigger food. It would be
safer to avoid the food altogether even if it is normally not a problem without
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 exercise. There have also been rare reports of symptoms occurring when the food is
eaten immediately after exercise.

• Food plus exercise and/or aspirin: A research team examined a patient with a history
of FDEIA related to eating wheat before exercise. They found that he also suffered a
reaction when aspirin was taken before eating wheat – even without exercising. The
combination of aspirin, wheat and exercise triggered symptoms that were even more
severe, but wheat alone did not trigger symptoms (Harada et al, 2001). The same
report describes the case of an 18-year-old man with FDEIA who suffered symptoms
with a combination of aspirin, shrimp and exercise. In other cases ibuprofen and other
non-steroidal anti-inflammatory drugs (NSAIDs) may act as the responsible co-
factor.

• Exercise and exposure to cold: Researchers reported on a 16-year-old Japanese boy

who had a four-year history of allergic reactions when he exercised in winter. Tests
showed it was the combination of cold and strenuous exercise that triggered the
symptoms. Food was not thought to be a factor in this case (Li et al, 2002).

• Cereal mites with exercise: A 17-year-old boy suffered anaphylaxis while jogging
after having eaten a Japanese pancake. The pancake mix, which had been stored for
several months after the package had been opened, was examined under a
microscope, and live mites were discovered. The researchers concluded that it was a
combination of eating the mites and exercise that caused the symptoms (Adachi et
al, 2013). One of our medical advisers tells us he saw the case of a boy who exercised
in the snow after eating a breakfast cereal from a packet which had been open for
many months. The boy suffered a severe anaphylactic reaction.

• Intolerance to non-steroidal anti-inflammatory drugs (NSAIDS): Painkillers such

as aspirin and ibuprofen should also be regarded as a possibility when the cause of an
allergic reaction is a mystery.

Diseases that mimic anaphylaxis

• 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.
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 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.

Tips and advice

If you suffer allergy-like symptoms but the cause is a mystery, keep a detailed account of
your experience. Important points to note down are:
• Where you were at the time of the reaction
• The time of day
• What you had eaten or drunk within the hours leading up to the reaction
• Whether you had taken a painkiller or other medication within a few hours before the
reaction
• Whether you were taking a medication known to be associated with allergic reactions
• Your general state of health
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 • Whether you were particularly hot, cold or stressed
• Whether you had been exercising at the time of the reactions or just before

All these details might help to build a picture of the problem and possibly identify a common
thread.

Some other things to consider

• Do you suspect that a food is responsible? If so, try to get a detailed list of the
ingredients of any foods, sweets or snacks eaten within the hour before the reactions.
• If a takeaway or restaurant meal is suspected, it will help your doctor find a cause for
the reaction if you obtain a full list of the ingredients.
• Have you considered latex as a possible trigger? Itchy or swollen lips after attempting
to blow-up a balloon is a common sign.
• Have you considered a medication as a possible trigger?

References

The following studies are referred to in the text:

Adachi YS, Itazawa T, Okabe Y, Higuchi O, Ito Y, Adachi Y, 2013. A case of mite-ingestion-
associated exercise- induced anaphylaxis mimicking wheat-dependent exercise-induced
anaphylaxis. Int Arch Allergy Immunol 2013 Jul 31;162(2):181-183.

Cox, F., Khalib, K. and Conlon, N. (2021), PEG That Reaction: A Case Series of Allergy to
Polyethylene Glycol. The Journal of Clinical Pharmacology. https://doi.org/10.1002/jcph.1824

COVID-19: the green book, chapter 14a: https://www.gov.uk/government/publications/covid-

19-the-green-book-chapter-14a

Fernando SL, 2009. Cold-induced anaphylaxis. J Pediatr. 2009 Jan;154(1):148-148.e1.

Harada S, Horikawa T, Ashida M, Kamo T, Nishioka E, Ichihashi M, 2001. Aspirin enhances the
induction of type I allergic symptoms when combined with food and exercise in patients with
food-dependent exercise-induced anaphylaxis. British Journal of Dermatology 2001: 145: 336-
339.

Leduc V, Moneret-Vautrin DA, Tzen JT, Morisset M, Guerin L, Kanny G, 2006. Identification of
oleosins as major allergens in sesame seed allergic patients. Allergy 2006 Mar;61(3):349-56.

Li M, Sayama K, Tohyama M and Hashimoto K, 2002. A case of cold-dependent exercise-

induced anaphylaxis. British Journal of Dermatology 2002; 147: 368–370.

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Makani H, Messerli FH, Romero J, et al, 2012. Meta-analysis of randomized trials of angioedema
as an adverse event of renin-angiotensin system inhibitors. Am J Cardiol 2012;110:383–391.

National Institute for Health and Care Excellence (NICE), Anaphylaxis: assessment and referral
after emergency treatment Clinical guideline [CG134] Published date: 14 December 2011 Last
updated: 24 August 2020

Resuscitation Council (UK), 2008. Emergency treatment of anaphylactic reactions: Guidelines

for healthcare providers. http://www.resus.org.uk/pages/faqAna.htm.

Sanchez-Borges M, Suarez-Chacon R, Capriles-Hulett A, Caballero-Fonseca F, Iraola V, and

Enrique Fernandez-Caldas E, 2009. Pancake Syndrome (Oral Mite Anaphylaxis). World Allergy
Organ J. 2009 May;2(5):91-6.

Tripathi A, Commins SP, Heymann PW and Platts-Mills TAE, 2014. Delayed anaphylaxis to red
meat masquerading as idiopathic anaphylaxis. J Allergy Clin Immunol Pract 2014;2:259-65

The following paper may also be useful: Lenchner KI, Ditto AM. 2004. Idiopathic Anaphylaxis.
Allergy Asthma Proc. 2004; 25 :S54-6

Reviewers

The content of this Factsheet has been Peer Reviewed by Prof John Warner, Emeritus
Professor of Paediatrics National Heart and Lung Institute, Imperial College London; Hon
Professor University of Cape Town; and Dr Tariq El-Shanawany, Consultant Clinical
Immunologist, University Hospital of Wales. We are not aware of any conflicts of interest in
relation to their review of this Factsheet.

Disclaimer

The information provided in this Factsheet is given in good faith. Every effort has been taken
to ensure accuracy. All patients are different, and specific cases need specific advice. There
is no substitute for good medical advice provided by a medical professional.

About the Anaphylaxis Campaign

The Anaphylaxis Campaign is the only UK wide charity to exclusively meet the needs of the
growing numbers of people at risk from severe allergic reactions (anaphylaxis) by providing
information and support relating to foods and other triggers such as latex, drugs and insect
stings. Our focus is on medical facts, food labelling, risk reduction and allergen management.
The Campaign offers tailored services for individual, clinical professional and corporate
members. Visit our website www.anaphylaxis.org.uk and follow us on Twitter
@Anaphylaxiscoms.

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