Anaphylaxis is a serious systemic hypersensitivity (allergic) reaction that is rapid in onset and may cause death.
Anaphylaxis can be a life-threatening condition that is broadly defined as a severe, generalised or systemic hypersensitivity reaction that is characterised by airway and/or breathing and/or circulation problems that is usually associated with skin and mucosal changes (i.e. urticaria and angio-oedema). Features of anaphylaxis are usually sudden with rapid progression so urgent assessment and management is vital.
Anaphylaxis is the most severe form of an allergic reaction that forms part of a spectrum. Allergic reactions are characterised by skin changes (e.g. urticaria) and subcutaneous/mucosal changes (e.g. angio-oedema). The crucial differentiating factor between these changes and anaphylaxis is the presence or airway, breathing, and/or circulatory dysfunction.
Two key principles:
The mortality associated with anaphylaxis is less than 1% in patients presenting to hospital.
The true incidence of anaphylaxis is difficult to quantify. It is estimated that 1 in 300 people will experience an episode of anaphylaxis during their lifetime with an incidence in Europe of 1.5-7.9 per 100,000 person-years.
The overall risk of recurrent anaphylaxis is estimated at 1 in 12 per year within the UK.
Anaphylaxis may be triggered by a very broad range of allergens.
A specific trigger is commonly identified in anaphylaxis but up to 30% of cases may be idiopathic (i.e. no known cause). The most commonly recognised allergens include food, drugs and venom (e.g. insect bites or stings).
The above causes typically result in an immunological reaction that is mediated by immunoglobulin E (IgE) leading to mast cell degranulation and release of chemical mediators (see pathophysiology). Some alternative immunological mechanisms have been identified (e.g. complement-mediated) as well as non-immunological mechanisms.
In non-immunological mechanisms there is direct activation of mast cells and basophils leading to release of chemical mediators such as histamine. Examples include:
The predominant mechanism of anaphylaxis is exposure to an allergen leading to IgE-mediated activation of mast cells and basophils.
Traditionally, the term ‘anaphylaxis’ was reserved for IgE-mediated reactions and ‘anaphylactoid reaction’ for non-IgE-mediated reactions. However, the two reactions are indistinguishable and the World Allergy Organization (WAO) now advises immunological anaphylaxis (e.g. IgE-mediated) and non-immunological anaphylaxis (e.g. direct mast cell activation).
We briefly review the formation of an IgE-mediated allergic reaction.
IgE is one of five types of antibody in the body. IgE, like all antibodies, are produced by B cells. IgE is normally involved in defence against parasitic disease, but is also central to the pathophysiology of ‘allergic’ disease. Allergy refers to an exaggerated immune response to an otherwise innocuous substance (e.g. pollen/nuts).
In development of an allergic response there is an initial process called sensitisation. After entry of an allergen into the body, it is taken up by antigen-presenting cells that interact with T-helper type 2 (Th2) cells and B cells within lymphoid tissue. This leads to allergen-specific IgE production by B cells. The released IgE then binds to mast cells and some basophils located around the body, particularly in the skin, gut and lungs.
Following sensitisation, patients may develop an allergic-reaction on re-exposure. If the patient is re-exposed to the same allergen and it diffuses in the proximity of these mast cells and basophils it can leading to binding to the IgE antibodies. Binding leads to cross-linking and aggregation that initiates intra-cellular signalling. If this signal is strong enough, it leads to activation and degranulation causing release of massive amounts of chemical mediators including histamine, tryptase, cytokines, prostaglandin and leukotrienes.
These chemical mediators act directly on tissue as well as recruit additional inflammatory cells (e.g. eosinophils). They cause local inflammation, vessel dilatation, loss of vascular integrity and fluid extravasation leading to oedema. The combination of oedema and massive vasodilatation can lead to airway obstruction, bronchoconstriction and reduced cardiac output. This culminates in marked hypoxia and hypotension that leads to anaphylactic shock.
Anaphylaxis is characterised by sudden onset airway and/or breathing and/or circulatory dysfunction often with typical skin/mucosal changes.
The sudden and rapid development of symptoms affecting the airway, breathing and/or circulation following exposure to an allergen is classic for anaphylaxis. A range of clinical features may be seen to affect different organ systems of which none are specific for anaphylaxis. It is the combination of features with rapidity of symptoms that suggests the diagnosis.
Patients with anaphylaxis should be assessed with an ‘ABCDE approach’ and here we present the clinical features in this manner.
Assessment of conscious level is vital. Decreased brain perfusion may reduce conscious level and compound airway obstruction. Features may include:
Cutaneous findings are often the first feature of anaphylaxis, but may be absent in 10-20% of cases. Signs may be subtle (e.g. patchy erythema only). The two classic signs are urticaria and angio-oedema:
Gastrointestinal clinical features may also be present due to degranulation of mast cells in the GI tract. In the absence of airway, breathing, and/or circulation problems they are unlikely to represent anaphylaxis.
Anaphylaxis is a clinical diagnosis based on rapid development of characteristic signs and symptoms.
All patients with suspected anaphylaxis require urgent assessment using an ‘ABCDE’ approach. Anaphylaxis should be suspected in any patient with sudden onset and rapidly developing airway and/or breathing and/or circulatory dysfunction that is usually accompanied by urticaria and/or angio-oedema.
A series of basic investigations should be requested including urgent bloods (e.g. full blood count, urea & electrolytes), arterial or venous blood gas, 12-lead ECG and chest x-ray. These investigations are not specific to anaphylaxis, instead they represent a routine set of investigations for any critically unwell patient.
Other investigations may be warranted depending on the suspected trigger or co-morbidities of the patient.
Mast cell tryptase is one of the major proteins released during activation and degranulation. This means its concentration will increase during an episode of anaphylaxis. Therefore, mast cell tryptase can be used as a surrogate marker of anaphylaxis and analysis of this protein is used in the follow-up of anaphylaxis. Importantly, it is NOT useful in the initial recognition and management of anaphylaxis.
Mast cell tryptase should be collected 1-2 hours after onset but no later than 4 hours as levels begin to fall and can be normal within 6-8 hours. A minimum of one sample should be taken, but ideally, three samples should be collected as follows:
Mast cell tryptase helps to confirm the diagnosis of anaphylaxis after the initial episode. However, a normal value does not exclude anaphylaxis. It can be useful because many conditions may resemble anaphylaxis (e.g. hereditary angio-oedema)
The principal pharmacological treatment of anaphylaxis is intramuscular adrenaline.
The emergency management of anaphylaxis should be in line with the Resuscitation council 2021 guidelines. In a patient with suspected anaphylaxis the following algorithm should be followed:
Adrenaline is the principal medication used to treat anaphylaxis. It is given as an intramuscular (IM) injection (even if the intravenous route is available) into the anterolateral aspect of the anterior thigh. The concentration of adrenaline should be 1:1000 that is equivalent to 1mg/ml. The dose depends on the age of the patient:
NOTE: Give 300 micrograms IM (0.3 mL) in a child who is small or prepubertal.
Adrenaline treats anaphylaxis by its action on two receptors:
A second dose of adrenaline may be given after 5 minutes if there is no improvement. If there is no improvement after two doses of adrenaline treatment should follow the refractory anaphylaxis algorithm in line with the resuscitation council guidance.
The use of anti-histamines was traditionally part of the initial management of anaphylaxis. However, they are currently NOT recommended as part of the initial management. They can be used to treat skin symptoms (e.g. urticaria/angio-oedema) that occur alongside anaphylaxis but use should not delay administration of adrenaline and IV fluids.
A second-generation non-sedating agent (e.g. cetirizine) should be given via the oral route. If the oral route is not available, chlorphenamine may be given intravenously or intramuscularly. This is a first-generation sedating anti-histamine.
The use of corticosteroids (e.g. intravenous hydrocortisone) was traditionally part of the initial management of anaphylaxis. The primary use was to prevent the late phase inflammatory response (i.e. biphasic reaction). However, there is little evidence they shorten protracted symptoms. Therefore, the routine use of steroids is no longer advised.
Corticosteroids may be considered for refractory reactions or ongoing asthma/shock after the initial resuscitation. Importantly, they should not be given in preference to adrenaline.
Patients with evidence of hypotension/shock or those that have a poor initial response to adrenaline should be given an intravenous fluid bolus. The initial bolus should be:
Further fluids should be given as necessary and recognise that large volumes of fluid may are required for patients with anaphylaxis (e.g. up to 5 litres in adults). With larger volumes of fluid, a balanced crystalloid (e.g. Hartmann’s) is preferred to 0.9% sodium chloride.
Defined as anaphylaxis requiring ongoing treatment despite two appropriate doses of adrenaline.
The exact mechanism of refractory anaphylaxis is poorly understood. However, it is likely due to a combination of delayed administration of adrenaline, ongoing release of inflammatory mediators or diminished response to adrenaline.
Patient with refractory anaphylaxis should be referred to the critical care team for ongoing support. The principal treatment is initiation of an adrenaline infusion. Repeated doses of intramuscular adrenaline should be given at 5 minute intervals whilst the intravenous infusion is being prepared and ongoing fluid resuscitation should be administered.
For more information, see the refractory anaphylaxis algorithm published by the resuscitation council.
This refers to the recurrence of symptoms several hours laters in the absence of exposure to the allergen.
The biphasic reaction is estimated to occur in around 5% of patients with anaphylaxis. The median time to developing a biphasic reaction is 12 hours. It can be difficult to distinguish this reaction from sustained anaphylaxis that had a transient response to adrenaline or further absorption of the allergen in the gastrointestinal tract (food allergies).
Risk factors for developing a biphasic reaction include:
Due to the risk of a biphasic reaction patients are traditionally observed for a period of 6-12 hours, however, fatal outcomes are very rare. More recently, depending on a patients risk of developing a biphasic reaction, observation may be for a shorter period of time.
Specific criteria are outlined in the resuscitation council guidelines on anaphylaxis that help to determine a patients risk of anaphylaxis. For considering early discharge (i.e. within 2 hours), several criteria must be met that includes already having unused adrenaline auto-injectors and knowing how to use them.
Information on discharge and follow-up in an allergy clinic are important following anaphylaxis.
Several broad principles are required prior to discharging a patient following an anaphylactic reaction.
All patients should be referred to an allergic clinic on discharge. Each patient will be reviewed by a clinical immunologist or allergist to determine whether the reaction was true anaphylaxis and the likely underlying cause. This should be conducted in an outpatient clinic once the patient is stable and discharged from hospital
Numerous test can be requested including mast cell tryptase to compare with the level at the time of the reaction, allergen-specific IgE antibodies and skin-prick testing.
Anaphylaxis is a life-threatening condition that can lead to death without urgent treatment.
Without treatment, anaphylaxis can be fatal but thankfully the mortality is estimated as <1% in patients presenting to hospital. Approximately 50% of deaths are due to circulatory collapse (shock) and 50% due to respiratory arrest.
Allergic reaction secondary to food are more likely to lead to respiratory arrest. Insect stings/bites and medications are more likely to lead to circulatory collapse.
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