Steven Montgomery (Junior Paediatric Clinical Fellow), Katarina Stefkova (Paediatric ST3), Shilpa Shah (Consultant Paediatrician), Craigavon Area Hospital

Anaphylaxis is a dreaded presentation to the Emergency Department – especially if there is an unknown allergen or non-classical presentation. The latter can cause confusion in diagnosis and delay in initiating life saving treatment. Despite recognition and appropriate initial management, there can be variation in practice in terms of how long a child is kept under observation for delayed or biphasic reaction. Then there are other common questions, such as the indication for prescribing adrenalin auto injectors for an unknown allergen, and the role of mast cell tryptase testing.

We attempt to answer these questions with the help of our patient, Anna.

Meet Anna

Anna is a 7 year old who has asthma, diagnosed when she was three years old. Her asthma triggers include viral illness and seasonal temperature change. She has no drug or food allergy. She has mild eczema, which flares up during winter. She hasn’t suffered any severe asthma exacerbations for the last year and is on 100 mcg twice daily of Beclomethasone inhaler. Her overall asthma management is good including inhaler technique and recognition of exacerbation. There is no family history of atopy.

Anna was out playing in the lawn of her back garden on a sunny mid-April afternoon. She suddenly started feeling itching in the back of her throat followed by some difficulty in breathing. She ran inside and asked her mom for her inhaler, and took 6 puffs of salbutamol. This helped to some extent. Then she felt light headed. Her mom noticed she appeared pale and gave her some water for hydration. Anna felt worse, and asked for her inhaler again because her chest felt tight. She appeared breathless. Her mother gave her another 10 puffs of the blue inhaler. She didn’t like how pale Anna was so called 999.

The ambulance arrived within moments. Anna was awake and alert but pale and sweaty. She had no stridor. There was no lip or tongue swelling but her throat felt very itchy. Her respiratory rate (RR) was 35/minute and she had nasal flaring and intercostal recessions with bilateral good air entry but extensive inspiratory and expiratory wheeze. Her oxygen saturation in air (FiO2) was 85%. She was started on oxygen and nebulized salbutamol. Her heart rate (HR) was 130/minute, capillary refill time (CRT) 3 seconds and Blood pressure (BP) was hard to obtain because the cuff available was large for her arm. The ambulance crew put the blue lights on and called ahead with a pre-alert call – ‘life threatening exacerbation of asthma’

Anna arrives into the Emergency Department resuscitation area where the paediatric team is waiting. She is awake but less alert that before. Her airway is patent with no stridor, lip or tongue swelling. Her RR is 39/minute and FiO2 (despite the salbutamol and oxygen) is still 85%. Her chest findings are the same. Her HR is up to 140/minute, CRT 3 seconds. Her BP is 99/45. The ED SHO was clarifying history of inhaled, contact or ingested allergen or a sting.

The ED consultant announces to the team – ‘this isn’t an asthma exacerbation. She is shocked and hypotensive – this is anaphylaxis’

Q1. What is anaphylaxis and how can it present?

Anaphylaxis is a severe, life threatening, generalised or systemic hypersensitivity reaction. Anaphylaxis can be immunologically or non-immunologically mediated (previously, immune mediated was called anaphylaxis and non-immune mediated was called an anaphylactoid reaction).

Anaphylaxis can present in multiple ways – an allergic reaction is considered to be anaphylaxis if it affects the airway, breathing or circulation of the patient. Below is a table that shows some of the typical findings in anaphylaxis, however, not all of these signs need to present to make the diagnosis.

If any of the above symptoms are present, anaphylaxis should be considered as a possible diagnosis.

Anaphylaxis is a systemic response caused by the release of immune and inflammatory mediators from mast cells and basophils. The binding of IgE to the mast cells and basophils activates them resulting in the release of several different mediators. One of these mediators is histamine, which stimulates vasodilation, which can result in tachycardia, hypotension and increased vascular permeability all of which can lead to shock.

This initial activation causes downstream activation of further metabolites one of which is prostaglandin D2. Prostaglandin D2 is a potent bronchoconstrictor and a peripheral vasodilator, which can be responsible for some of the symptoms of anaphylaxis. These immune and inflammatory mediators can cause systemic symptoms, which can occur in a matter of minutes to up to an hour.

Anna receives adrenalin, hydrocortisone and an antihistamine as per the APLS Anaphylaxis pathway. She is also put in the ‘leg raise’ position to prevent empty ventricle syndrome She gets a fluid bolus and more nebulized salbutamol.

She has a good response to her treatment and her obs improve, the wheeze clears, and she looks less pale. She feels much better and asks for a snack! Anna moves to the paediatric ward for close observation.

The Junior Paediatric doctor explains to Anna’s mom that Anna has suffered a strong allergic reaction to something. ‘We aren’t sure what triggered it – but we would like to observe Anna for at least another 6-8 hours in case she has a ‘biphasic’ reaction.’

Q2. What is the risk of a biphasic anaphylactic reaction, and how long should we observe in hospital after successfully treating anaphylaxis?

Biphasic anaphylaxis is recurrent anaphylaxis without a new trigger, occurring usually 1 to 72 hours after resolution of an initial anaphylactic episode. Estimates of rate of biphasic anaphylaxis occurring vary from <1% to 20%.
Recommendations following a systematic review and meta-analysis undertaken by the Joint Task Force Practice Parameters (JTFPP) suggest that biphasic anaphylaxis is associated with a more severe initial presentation or when repeated doses of adrenalin are required with the initial presentation. Additional risks include wide pulse pressure, unknown anaphylaxis trigger or drug trigger in children. Prompt and adequate treatment of anaphylaxis appears central to reducing biphasic anaphylaxis risk. 

Evidence around optimal duration of observation for a biphasic reaction is lacking but the JTFPP suggest discharge after a 1-hour asymptomatic period in patients without severe risk features. In those with high-risk features or poor self-management skills, a 6-hour or longer period of observation may be appropriate. Regardless of severity, all patients treated for anaphylaxis should be observed at least until symptoms and signs have fully resolved. 

Although it is important to highlight the risk of biphasic anaphylaxis to the highest risk groups, it is important to educate all patients regarding the chance of a biphasic reaction, allergen avoidance, symptom recognition, prompt management with adrenalin auto injector and prompt follow up with an allergy specialist. 

Anna remained well and did not require any further inhaled bronchodilator or intramuscular adrenalin.

On the ward, the paediatric registrar asks, ‘Should we do a mast cell tryptase?’

Q3. What is the role and indication for serum mast cell tryptase level in acute presentation of anaphylaxis?

Mast cell tryptase is an enzyme released during mast cell degranulation that occurs in anaphylaxis. This is usually triggered by antigens cross-linking cell surface immunoglobulins (IgE). It is released immediately during an anaphylactic reaction, so a serum level should be taken as soon as possible. A second sample should follow within 1-2 hours, but no later than 4 hours. Limited adult studies have shown that measurement of peak mast cell tryptase, (compared to clinical diagnosis only) had specificity of 87-100% and sensitivity of 35-95%. Serial sampling increased the specificity to 98% and sensitivity to 73% in one study.

The degree of elevation of mast cell tryptase correlates with the clinical symptoms. However, normal results do not exclude anaphylaxis, especially if caused by food.

Mast cell activation is not always IgE mediated. Non-immunological, chemical and physical stimuli can all cause mast cell degranulation. Systemic mastocytosis can also cause chronically elevated mast cell tryptase levels.

A further serum sample should be performed, which is usually done when the patient is followed up at an allergy clinic. Comparison of normal serum with peak serum mast cell tryptase was reported to have 91% specificity and 73% sensitivity, compared to clinical diagnosis only.

The pathophysiology of anaphylaxis is complex, and the studies available on measurement of mast cell tryptase are mostly observational and involve the adult population. The measurement of mast cell tryptase is also an expensive test to perform.

Taking all of this into the account, the NICE guidelines (CG143) recommend measuring mast cell tryptase in children under 16 year old in cases when anaphylaxis is thought to be caused by venom, drugs or the cause of the reaction is unclear. The first sample is recommended as soon possible after emergency is initiated and a second sample ideally 1-2 hours but no later than 4 hours after onset of symptoms

Anna is back to normal in a few hours, and wants to get home. Her mom is very anxious about Anna having anaphylaxis again, and what she would do.

She asks, ‘do you think I should get one of those adrenalin pens for Anna? Also, will she be followed up by the allergy team?’

Q4. Discharge and follow up of a presumed anaphylaxis with an unclear trigger

NICE advise that patients should be given information about anaphylaxis, including what signs and symptoms to look out for in future in the case of a future reaction. They should also be told about the possibility of a bisphasic reaction and if they have concerns to return to hospital for the possibility of further treatment.

In the case of an unknown allergen, patients and parents should be discharged with an adrenaline auto injector and given a demonstration on how and when to use this device, they should also be advised that if they ever use the auto injector that they must present to hospital via 999.

In the case of an unknown allergen it may also be useful for the family to keep a diary of what foods they ate, any activities undertaken or any other common links between reactions to help try and identify a possible trigger.

Any child who has needed treatment for a suspected anaphylactic reaction should be referred to the specialist allergy team. Information should be given to the family about where, and an estimate to when this appointment will take place.

As with all diagnoses, it’s important to give advice leaflets that patients and their parents can read and refer back to if they have any questions. Information about appropriate family support groups available locally is also useful to provide!

Please note, ‘Anna’ is a fictional patient and any similarities to real life cases are purely coincidental.

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