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Next Lesson - Food Allergy
Contents
Abstract
- Type 1 hypersensitivity describes allergic reactions.
- They are triggered by an abnormal adaptive immune response against allergens (substances that trigger an allergic reaction).
- They involve Th2 cells (type 2 T helper cells), IgE (the class of antibody involved in allergy) and mast cell activation. Mast cells are immune cells in the tissues that release histamine, a chemical that causes many allergy symptoms.
- Clinical presentation of type 1 hypersensitivity reactions can be localised or systemic. A severe systemic reaction with airway, breathing or circulation problems is anaphylaxis.
Core
Type 1 hypersensitivity reactions are immune reactions that are caused by an environmental, non-infectious allergen (a substance that triggers an allergic reaction). Type 1 hypersensitivity is commonly called allergy. It can cause a localised reaction (affecting one part of the body) or a systemic reaction (affecting the whole body). Anaphylaxis is a serious systemic reaction that is usually rapid in onset and may cause death. It is recognised by life-threatening problems with the airway, breathing and/or circulation. A widespread reaction without these problems, such as generalised hives (urticaria) alone, is not anaphylaxis. Exposure to the trigger (allergen) can come in many forms, such as inhalation, ingestion, injection or physical contact. Most reactions develop within minutes, and the timing depends on the trigger. Injected allergens (for example an intravenous drug or an insect sting) cause a faster onset than swallowed ones (for example food or an oral drug). Symptoms can also appear after a few hours.
Allergens can be divided into several categories. Grouping them like this helps when taking an allergy history and advising on how to avoid triggers:
- Seasonal environmental exposure: tree and grass pollens
- Perennial (year-long) environmental exposure: house dust mites, animal dander (tiny flakes of skin and hair) and fungal spores (tiny reproductive cells released by moulds)
- Accidental exposure, which can include:
- Food: peanuts, eggs
- Iatrogenic (caused by medical treatment): penicillin, latex
- Other: venom from insect stings
When the immune system is first exposed to the allergen, it activates Th2 (T helper 2) cells. These T helper cells stimulate B cells (lymphocytes that make antibodies) to produce IgE antibodies. The IgE binds to mast cells (immune cells found in the tissues) and basophils (white blood cells in the blood that, like mast cells, can be triggered by the allergen). This first exposure usually causes no symptoms. On later exposure, the allergen triggers these cells to release chemicals. These are histamine (stored ready-made in the cell), leukotrienes (made when the cell is triggered) and cytokines (small proteins that signal to other immune cells).
Leukotrienes are potent constrictors of the airways (bronchoconstriction, narrowing of the airways). Histamine and cytokines cause vasodilation (widening of blood vessels) and increased vascular permeability (the vessel walls become leaky). The effects overlap, and histamine can also narrow the airways. Together, these effects cause inflammation, because blood flow to the area increases. If the contact with the allergen is localised, the response is usually a mild, localised irritation. If the reaction is systemic, it can cause anaphylactic shock (when the circulation fails to supply the tissues with enough blood), which can be life-threatening. Reactions to allergens can therefore be very dangerous. An inhaled allergen can be life-threatening even when the inflammation stays in the lungs. An allergen injected into the bloodstream can cause massive widespread effects.
It is important to note that type 1 hypersensitivity reactions involve a sensitisation phase. On first exposure, allergen-specific IgE (IgE that recognises that particular allergen) is generated and binds to mast cells, usually without symptoms. Clinical reactions typically occur on subsequent exposure when the allergen links two neighbouring IgE molecules on the mast cell surface (cross-linking). This triggers mast cell degranulation, where the cell releases the chemicals stored in its granules.
Allergic diseases have become much more common over the past century, especially in high-income countries. Modernisation and Westernisation are linked to more inflammatory disease, including allergy. One idea, the Hygiene Hypothesis, is that less exposure to infections and microbes early in life may make allergy more likely. This is an association. It has not been proven that hygiene is the cause. David P. Strachan first described the Hygiene Hypothesis in 1989. He observed that children with more older siblings had a lower incidence of allergic conditions such as hay fever. He suggested that infections passed on by contact with older siblings might give some protection.
A Western lifestyle is linked to lower microbial diversity in the microbiome (the community of microbes living in and on the body). Diet, hygiene standards and daily habits may all play a part. This loss of diversity can disrupt the symbiotic relationships (mutually helpful partnerships between microbes and the body) on the mucosal surfaces (the moist linings of the body), mainly in the gut. This disruption of the microbiome is known as dysbiosis. Dysbiosis has recently become a focus of research. We are only beginning to understand how the microbiota may regulate the immune system. Links have been suggested between dysbiosis and other immune-related diseases. Examples are listed below:
- Crohn’s disease and ulcerative colitis (inflammatory diseases of the bowel)
- type one diabetes mellitus
- coeliac disease (an immune reaction to gluten)
- multiple sclerosis (an immune-mediated disease of the brain and spinal cord)
These are associations only.
Allergic reactions often affect the skin. This is because mast cells are abundant in the dermis (the layer of skin below the surface), and all type 1 hypersensitivity reactions involve mast cell degranulation. In the skin, this degranulation appears as an urticaria rash (hives), which is raised and itchy. Skin changes can be subtle or absent in 10 to 20% of anaphylactic reactions, so a reaction without a rash can still be serious. Atopic dermatitis (eczema) is a long-term condition that causes itchy, dry skin. Atopic means having a tendency to allergic disease. Eczema is not simply caused by prolonged exposure to an allergen. It is more likely if a parent has eczema, or if the patient or a close family member has asthma or hay fever. Allergens such as pollen, house dust mites or certain foods can make it worse.
Angioedema is swelling of the deeper tissues, most commonly in the eyelids and lips and sometimes the tongue and throat. In an allergic reaction it is caused by mast cell degranulation within the deeper layer of the dermis and mediated primarily by histamine released from mast cells. Swelling of the tongue and throat can cause constriction of the upper respiratory airway. Allergic angioedema with airway, breathing or circulation problems is managed as anaphylaxis. Not all angioedema is allergic. In hereditary angioedema (an inherited form), adrenaline, corticosteroids (steroid medicines that reduce inflammation) and antihistamines are ineffective.
Finally, systemic activation of mast cells can result in anaphylaxis. Common triggers include food (for example peanuts), drugs (for example antibiotics) and venom from insect stings. Food is the most common cause in young people. Less common triggers include latex. Anaphylaxis can cause hypotension and cardiovascular collapse, as well as angioedema and bronchial constriction (narrowing of the airways). It is a life-threatening emergency. When the circulation fails, it is called anaphylactic shock.
Call for an ambulance and ask for help from colleagues. Use the ABCDE approach (Airway, Breathing, Circulation, Disability, Exposure) to assess the patient. Treatment of anaphylaxis requires immediate intramuscular injection of adrenaline into the anterolateral aspect of the middle third of the thigh (the front and outer side). People at risk of anaphylaxis are advised to carry two in-date autoinjector pens (pre-loaded devices that each deliver a fixed dose of adrenaline) with them at all times. One brand is EpiPen®. Healthcare professionals draw up the dose from 1 mg/mL (1 in 1000) adrenaline. The dose depends on age: 500 micrograms (0.5 mL) for adults and children over 12 years, 300 micrograms (0.3 mL) for children aged 6 to 12 years, 150 micrograms (0.15 mL) for children aged 6 months to 6 years, and 100 to 150 micrograms (0.1 to 0.15 mL) for babies under 6 months. The dose is repeated after 5 minutes if there is no improvement. If in doubt, give adrenaline and seek expert help. Remove the trigger if possible, for example by removing a bee sting. A patient with low blood pressure should lie flat, with or without the legs raised. A patient with breathing difficulty may prefer to sit semi-upright, which makes breathing easier. Where skills and equipment are available, give oxygen at the highest concentration possible.
Adrenaline is an effective initial treatment for anaphylaxis because it reverses many of the symptoms:
- Causes peripheral vasoconstriction, which counteracts the vasodilation caused by histamine and cytokine release and acts to raise blood pressure.
- Prevents ongoing fluid loss from the blood vessels into the surrounding tissues (the extravascular space) by reducing vascular permeability (how leaky the vessel walls are).
- Reverses bronchoconstriction by dilating (widening) the airways, to help them remain functional.
- Increases the force of contraction of the heart muscle (myocardial contraction).
- Inhibits further mast cell degranulation to try to prevent further symptoms and deterioration.
Treatment should be given as soon as possible. For this reason, people with known allergies are taught how and when to use their autoinjectors. When possible, basic observations should be monitored, e.g. pulse, blood pressure, oxygen saturation, temperature, respiratory rate and ECG.
While adrenaline is the most important and life-saving treatment of anaphylaxis, it is important to remember that adrenaline alone will not remove the allergen. Adrenaline has a very short half-life (the time taken for the amount of drug in the body to halve), so multiple doses may be required. Repeat the intramuscular dose after 5 minutes if airway, breathing or circulation problems persist. If there is no improvement after two appropriate doses, the patient has refractory anaphylaxis (anaphylaxis that is not responding to treatment). Their care should be escalated quickly. These patients are treated with an intravenous adrenaline infusion, which should only be given by experienced specialists in a setting where the patient can be carefully monitored. A biphasic allergic reaction may occur, where symptoms return after complete recovery with no new exposure to the allergen, even after appropriate initial treatment. NICE defines this as a recurrence within 72 hours. It occurs in around 5% of patients. Patients are therefore observed after all symptoms have resolved. Observation is for at least 6 hours if two doses of intramuscular adrenaline were needed or there is a history of biphasic reaction. It is for at least 12 hours in higher-risk cases, such as more than two doses of adrenaline, severe asthma or severe respiratory compromise. Discharge after 2 hours can be considered only if all of the following apply:
- There was a good response to a single early dose of adrenaline.
- Symptoms have completely resolved.
- The patient already has two in-date autoinjectors.
- There is adequate supervision.
Other Treatments in the Acute Phase
Over the years there have been many medications and strategies suggested to aid adrenaline use in the acute phase of an allergic reaction. Some of these are listed below:
- Steroids: corticosteroids such as hydrocortisone (given into a vein) are no longer advised for the routine emergency treatment of anaphylaxis. They must not be given in place of adrenaline. There is little evidence that they prevent biphasic reactions. They can be considered after initial resuscitation for refractory reactions or ongoing asthma or shock.
- Antihistamines: drugs that block the effects of histamine. They are not recommended as part of the initial emergency treatment, because they do not treat airway, breathing or circulation problems. Once the patient is stable, a non-sedating oral antihistamine such as cetirizine (in preference to chlorphenamine, an older antihistamine that causes drowsiness) may be considered, especially for persistent skin symptoms (hives or angioedema).
- Intravenous fluids: support the circulatory system by increasing the intravascular volume (the amount of fluid inside the blood vessels), helping to counteract the negative consequences of vasodilation. They should be given to patients with hypotension or shock, or if there is a poor response to the first dose of adrenaline.
- Bronchodilators: drugs that widen the airways, helping to reverse bronchoconstriction. Inhaled salbutamol and/or ipratropium bromide can be considered for persisting breathing problems. They should not be used instead of further adrenaline.
Long-Term Management of Allergies
Living with a life-threatening allergy can be very limiting (debilitating), so several therapies have been developed to try to reduce its severity.
Pharmacological treatments depend on the condition being treated. Antihistamines help to relieve hay fever and skin symptoms such as hives. Leukotriene receptor antagonists (for example montelukast) are used to prevent asthma symptoms and to relieve seasonal allergic rhinitis (hay fever) in patients with asthma. Corticosteroids (steroid medicines that reduce inflammation) are a main treatment for asthma and are also used as nasal sprays for hay fever. Anti-IgE monoclonal antibody therapy (omalizumab, a laboratory-made antibody that targets IgE) is used for severe persistent allergic asthma and for severe chronic spontaneous urticaria (long-lasting hives with no clear trigger). These medicines do not replace adrenaline in anaphylaxis.
Allergen desensitisation therapy (also called allergen immunotherapy) uses medicines made from allergen extracts. The patient is given gradually increasing doses over time, so the body gets used to the allergen and does not react so badly. It can be used for bee and wasp venom allergy, to reduce the risk of severe reactions to later stings. Extracts of house dust mite, grass pollen and tree pollen can reduce symptoms of allergic rhinoconjunctivitis (inflammation of the nose and eyes). House dust mite extracts can also be added to regular treatment for allergic asthma caused by house dust mite. Evidence for cat and dog dander extracts is more limited, and study results have been mixed. In peanut allergy, desensitisation with peanut protein was offered to some children and young people using a peanut protein powder called Palforzia. Palforzia has been discontinued in the UK: no new patients will start it, and people already taking it can continue until March 2027. Healthcare professionals discuss other treatment options with these patients. Desensitisation is carried out in a controlled environment where the patient can be monitored for signs of anaphylaxis and treated promptly to reduce the risks. The dose is raised in stages (the build-up phase) until a maintenance dose is reached, and the maintenance dose is then continued. In studies of venom immunotherapy, side effects occurred in both phases, but most were mild.
Edited by: Dr. Maddie Swannack
Reviewed by: Dr. Thomas Burnell and Dr. Marcus Judge
Quiz
- 3430
