Buku Medicine

Adrenaline prescribing

From the 2016 BSACI Guidelines for adrenaline prescription (Please see website below for full guidelines)

Patients at risk of anaphylaxis that should be considered for long-term provision of an adrenaline auto-injector include those;

who have suffered a severe systemic reaction where the allergen cannot be easily avoided
who are allergic to high-risk allergens, for example nuts with other risk factors (such as asthma), even if the reaction was relatively mild
who had a reaction in response to trace amounts of allergen/trigger
who cannot easily avoid the allergen
with continuing risk of anaphylaxis (e.g. Food dependent, exercise-induced)
with idiopathic anaphylaxis
with significant co-factors (e.g. asthma in food allergy, raised baseline serum tryptase)

Adrenaline auto-injector dosing: Standard adult adrenaline autoinjectors are available in the form of JEXT or Epi-pen. A standard dose is 300mcg per injection. Some patients may require 500mcg based on weight and other risk factors. Currently, the only manufacturer for the high dose pens is Emerade, but supplies have been low for many months. All patients should have training in how to use these pens. Videos on the manufacturer websites can be used and “dummy pens” given through the local allergy unit for practice. Any patient being issued adrenaline autoinjectors should be referred to the Allergy Department for formal review.

Link for JEXT: Video demonstrations
Link for Epi-Pen: EpiPen® Explained: How It Works
Link for emerade: Instruction video for Emerade adrenaline auto-injector for anaphylaxis

References

https://www.bsaci.org/wp-content/uploads/2020/01/Ewan_et_al-2016-Clinical_26_Experimental_Allergy.pdf

Angioedema

General Principles

Angioedema is a transient localised swelling of the skin and/or mucosa.

If a patient presents with isolated angioedema, the first step is to determine the mechanism, i.e. mast-cell or bradykinin mediated and refer appropriately (likely mast-cell mediated = allergy services; likely bradykinin mediated = immunology services). Much of the specific management will be undertaken by the allergy/immunology clinic, but a thorough history trying to delineate the two pathologies should be undertaken by all encountering cases of angioedema.

Mast-cell-derived inflammatory mediators e.g. histamine increase vascular permeability that triggers a swelling which:
- Peaks within minutes to a few hours.
- Responds to antihistamines.
- Presents with localised pruritus and/or urticaria.
Bradykinin is produced by the kinin-kallikrein pathway. C1 inhibitor (C1i) (of the complement cascade) inhibits this pathway. Failure of C1i therefore results in an overproduction of bradykinin which increases vascular permeability that triggers a swelling which:
- Peaks over many hours/days
- Does not respond to antihistamines
- Is not associated with pruritus/urticaria (though may have a tingling prodrome).
- Frequently affects the gastrointestinal mucosa resulting in abdominal pain +/- N&V +/- diarrhoea ( please consider in patients with unexplained abdominal pain as unfortunately, exploratory laparotomies are common in bradykinin-mediated angioedema patients).
- May be hereditary

Subtypes

Mast-cell Mediated angioedema

Manage acutely with antihistamines, steroids, trigger avoidance advice +/- adrenaline autoinjectors in cases featuring anaphylaxis.

Allergic (IgE-mediated) angioedema. Usually occurs alongside urticaria, but ~1% of allergies occur as isolated angioedema.
Pseudoallergic (non-IgE mediated) angioedema. Most often seen with opiates, radiocontrast, and NSAIDs including aspirin. These reactions usually, but not always, occur alongside urticaria. Treatment is the same as for allergic angioedema however desensitisation protocols for NSAIDs exist and can be discussed with the allergy team.

Bradykinin Mediated angioedema

Drug induced angioedema – Most commonly caused by ACE inhibitors which inhibit bradykinin degradation. Usually affects face/upper airway. Angioedema usually occurs within the first 3 months of starting the causative drug but may begin years after stable therapy. Rarer causes include angiotensin-receptor blockers, and DPP4 inhibitors (aka gliptins).
- Management is via trigger avoidance and protection of airways. Hereditary/acquired angioedema should also be investigated for in these patients (see below).
C1 inhibitor deficiency angioedema – Attacks can be triggered by stress, infection, trauma (e.g. dental work), and hormonal changes in women.

All patients with isolated angioedema should have serum C4, C1i level, C1i function, C1q, C1q autoantibody, plus C1i autoantibody (if available) performed ideally during an attack. Those at risk of acquired angioedema (i.e. malignancy/autoimmune disease) should also be investigated as appropriate. Most of these tests will be performed through immunology clinics but if encountering an acute episode, consider testing for these if possible.

Many options are available for pharmacological treatment with specifics beyond the scope of this module. Clinical immunology should prescribe acute therapy (e.g. Berinert/Cinryze/Ruconest/Icatibant), and if necessary long-term prophylaxis (e.g. Danazol/Berinert/Cinryze). Patients should have emergency and pre-surgical/dental work management plans.

Other angioedema conditions

Hereditary angioedema (autosomal dominant). Most patients present by adolescence. Attacks usually affect the skin peripherally or GI tract, and less commonly the face/upper airway, however multiple sites may be affected at once.

Acquired angioedema. Secondary to lymphoproliferative disease (67%), autoimmune disease (8%), other malignancies (6%). Most patients present in or after the 4th decade Attacks more often affect the face than the limbs, and less commonly the GI tract. Underlying cause should be treated as appropriate.

Chronic idiopathic angioedema without urticaria (in whom other causes have been ruled out). Trial on antihistamines (+/- montelukast), or tranexamic acid. Response to either will suggest the underlying mechanism and should be treated appropriately. Chronic idiopathic angioedema with urticaria is mast-cell mediated (see section on chronic spontaneous urticaria for further information).

Anaphylaxis

Quick tip; IM adrenaline is first-line treatment for anaphylaxis – not corticosteroids (which are now no longer part of anaphylaxis treatment) and anti-histamines (which are a third line treatment)

Anaphylaxis is a potentially life-threatening allergic reaction. Anaphylaxis is highly likely when any ONE of the following three criteria is fulfilled:

1) Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)

AND AT LEAST ONE OF THE FOLLOWING:

Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, hypoxemia)
OR Reduced BP* or associated symptoms of end-organ dysfunction (eg, hypotonia, collapse, syncope, incontinence)

2) TWO or more of the following that occur rapidly after exposure to a LIKELY allergen for that patient (minutes to several hours):

Involvement of the skin or mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula)
Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, hypoxemia)
Reduced BP* or associated symptoms (eg, hypotonia, collapse, syncope, incontinence)
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)

3) Reduced BP after exposure to a KNOWN allergen for that patient (minutes to several hours):

Infants and children - Low systolic BP (age-specific)* or greater than 30% decrease in systolic BP
Adults - Systolic BP of less than 90 mmHg or greater than 30% decrease from that person's baseline

* Low systolic blood pressure for children is defined as: Less than 70 mmHg from 1 month to 1 year. Less than (70 mmHg + [2 x age]) from 1 to 10 years. Less than 90 mmHg from 11 to 17 years.

(Information above taken from; Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006; 117:391.)

Follow the Resuscitation Council UK algorithm for anaphylaxis management:

Refractory anaphylaxis has a separate algorithm

NB – IM adrenaline is first-line treatment for anaphylaxis – not corticosteroids (which are now no longer part of anaphylaxis treatment) and anti-histamines (which are a third line treatment)

Investigations

Mast cell tryptase: Preferably as soon as possible to the time of the allergic reaction (within 1 hour), 3 hours and at 24 hours after the reaction.
Complement C3, C4 if angioedema is prominent without urticaria.
Further investigations assessment for the specific allergen are tested at least 6 weeks after the index reaction eg. Specific IgE to peanut or skin prick testing. Please discuss with the Allergy Team which tests to request. When requesting a RAST test, this needs to be specific to the potential allergen identified from the clinical history.

Referral

The National Institute for Health and Care Excellence (NICE) have guidelines specific for anaphylaxis which include the assessment and referral of patients suspected to have had anaphylaxis. Specifically:

All patients should be referred to a specialist clinic for allergy assessment.
Offer patients (or, if appropriate, their parent and/or carer) an appropriate adrenaline injector as an interim measure before the specialist allergy assessment (unless the reaction was drug induced).
Patients prescribed adrenaline auto-injectors (and/or their parents/carers) must receive training in their use, and have an emergency management or action plan.

Information to include in an Allergy referral:-

- Exact clinical symptoms

- Allergens involved (ingredient lists/venom/drugs etc)

- Amount of allergen exposed to (e.g. nut trace vs five peanuts)

- Objective signs of allergy (discharge or A&E notes, observations at presentation)

References

NICE Guideline: https://www.nice.org.uk/guidance/cg134

Type I/IgE mediated

Quick Tip; Large local reactions to bites/stings do not usually need allergy referrals (if no systemic features)

IgE mediated reactions/Type 1 hypersensitivity reactions are due to antigen exposure (eg. peanut protein in peanut allergy) causing IgE-mediated activation of mast cells and basophils, with release of vasoactive substances, such as histamine, prostaglandins, and leukotrienes. These are immediate reactions and cause clinical features of an IgE mediated reaction eg. anaphylaxis, angioedema, bronchospasm, urticarial (hives) and hypotension, present within an hour of allergen exposure.

Food

Any substance may cause anaphylaxis, however some foods are much more common causes than others. The most common causes of food allergy include:-

Legumes: peanuts (and related legumes, soya and other beans/peas)
Tree nuts: (walnuts, almond, cashew, hazelnut etc.)
Shellfish and fish
Egg
Cow’s milk

Most allergens involved in food allergy are heat stable and acid stable (stomach acid). Please refer the patient to the Allergy clinic for further investigation.

Venom

Systemic reactions to bee and wasp stings should be referred to the Allergy clinic for further investigations and management. A baseline tryptase should be checked in these patients and adrenaline prescription considered.

Large local reactions are common and due to the nature of venom injected, rather than an allergy. Large local reactions do not usually require further investigations and should be treated with antihistamines and steroids.

Allergic Rhinitis/Rhinoconjunctivitis

Allergens causing perennial symptoms:

House dust mites (D Pteronyssinus or D farinae)
Animal Dander

Allergens causing seasonal symptoms

Grasses
Trees
Weeds
Moulds

Refer patients to the allergy clinic with suspected symptoms on inhalant allergen exposure, not controlled by maximum medical therapy

Antihistamines – taken daily, such as cetirizine 10mg twice daily
Steroid nasal spray – take regularly for at least 6 weeks with the correct technique (head bent down to chest and nozzle pointed slightly away from midline). E.g. Fluticasone two puffs in each nostril daily.
Eye drops such as sodium cromoglycate (preservative free) or Olopatadine up to four times a day

Additional therapies that can be helpful include nasal/sinus rinse, combination nasal spray with antihistamines (e.g. Azelastine/fluticasone ‘Dymista’) and ipratropium nasal sprays for rhinorrhoea. Desensitisation therapy may be offered by the Allergy Clinic for some inhalant allergens in the form of sublingual or subcutaneous immunotherapy, usually taken over three years.

Oral Allergy Syndrome

Oral allergy syndrome (OAS) is caused by IgE to the heat-labile allergens in fruits and vegetables, which are highly cross-reactive. OAS occurs in people who have pollen allergy (although not all patients have obvious hay fever or seasonal allergy symptoms). Patients are often sensitised to the Bet v1 birch pollen allergen. Patients typically report itching and/or mild swelling of the mouth and throat immediately following ingestion of certain uncooked fruits (including nuts) or raw vegetables. Systemic reactions are rare.

Investigation of OAS:

Clinical history confirming reproducibility of symptoms to raw fruit or vegetable. Absence of clinical symptoms on eating a cooked form of the fruit or vegetable. For example a patient has an itchy mouth after eating a raw apple, however tolerates apple in an apple pie baked at a high heat in the oven.
Skin prick testing does not reliably identify the allergen as the antigens are labile.

Treatment:

Dietary review and avoidance of trigger foods in their raw form.
May require an oral antihistamine during mild reactions. Prednisolone 20mg as a stat dose can be given if severe mucocutaneous swelling.

Referral:

Patients with any of the following characteristics should be referred to an allergy expert for further evaluation:

Definite or possible systemic symptoms.
Patients who report oropharyngeal symptoms but have no history of seasonal allergic symptoms to suggest pollen allergy, since these patients may have a primary food allergy.
Patients with reactions to foods that carry a higher risk of systemic reactions, such as peanuts, tree nuts, and mustard. In addition, peach is associated with systemic reactions in the Mediterranean region, due to the sensitization to lipid transfer proteins (LTPs).

Urticaria

General Principles

Urticaria aka hives, are pruritic wheals (i.e. transient, raised lesions caused by dermal oedema) with or without surrounding erythema (aka “flare”). They are the result of mast cell degranulation.

Urticaria can be classified by frequency, i.e. acute (<6 weeks) vs chronic (regular occurrence >6 weeks), and by aetiology, i.e. inducible vs spontaneous.

Urticaria often occurs alongside angioedema and investigations/management are the same (the exception being in life-threatening angioedema – see “anaphylaxis management”). Isolated angioedema requires additional investigations and is explored separately.

Subtypes

Acute Inducible Urticaria (+/- angioedema)

Acute inducible urticaria should be managed with removal of the trigger if possible (e.g. extract wasp sting), antihistamines +/- topical/oral steroids. It is more likely than other forms to be associated with life-threatening angioedema, i.e. anaphylaxis. Severe refractory, or anaphylactic episodes should result in referral to allergy. Triggers include:

Acute viral or bacterial infection, especially in children
Food allergy, e.g. nut, shellfish, cow’s milk allergy,
- Wheat-dependent exercise-induced anaphylaxis = gluten ingestion prior exercise can trigger urticaria/angioedema and possibly anaphylaxis. sIgE to ω5-gliadin needed for diagnosis-this will be tested by allergists if suspected. Tx = avoid exercise within 4 hours of eating wheat, pre-medicate with antihistamines and an Epipen for all (high risk).
Drug allergy, e.g. penicillins
Drug pseudoallergy, e.g. NSAIDs, opiates
Vaccination, e.g. tetanus/diphtheria toxoids (5-13% of recipients), Pfizer/AZ COVID vaccines.
Bee/wasp stings.

Chronic Inducible Urticaria (+/- angioedema)

Chronic inducible urticaria only occurs on exposure to specific triggers. It can usually be managed with avoidance strategies, antihistamines +/- short courses of topical/oral steroids. Triggers include:

Cold urticaria
Solar urticaria
Cholinergic urticaria (caused by heat/emotion/exercise)
Vibratory urticaria
Aquagenic urticaria
Pressure urticaria
Dermographism aka skin-writing, i.e. hives following scratch/stroking (a form of physical urticaria)
Pollen urticaria (often seen in hayfever aka allergic rhinitis)

Acute Spontaneous Urticaria (+/- angioedema)

Acute spontaneous urticaria has no identifiable cause and resolves in <6 weeks. It should be treated with antihistamines +/- short courses of topical/oral steroids. 1 in 5 individuals will have such an episode at least once in their life.

Chronic Spontaneous Urticaria (+/- angioedema)

Chronic spontaneous urticaria has no obvious trigger. It may be associated with anti-thyroid peroxidase antibodies (anti-TPO) in which case it is termed, “autoimmune urticaria”, though the treatment protocol is unchanged. 80% resolve after 10 years, but this is less likely with concomitant angioedema or anti-TPO. This can usually be managed in primary care with antihistamines but refractory cases should be referred to allergy.

Investigations

FBC, U&Es, LFTs, Thyroid function, Ferritin, B12, Folate, Vitamin D.
Baseline mast cell tryptase to rule out systemic mastocytosis. If raised above local reference range (usually >15g/L) consider haematology referral +/- c-Kit genetic mutation screen as per local guidelines.
Specific IgEs to any possible triggers gleaned from history, e.g. specific foods, grass/tree pollens, animal dander. Not to be tested routinely as chronic urticaria is rarely due to allergy.
Anti-TPO. If positive, for annual TFTs due to risk of autoimmune thyroid disease.

Management

Antihistamines: depending on regularity, can either be regular or PRN. Cetirizine 10-20mg OD/BD which can be tapered as appropriate. Alternatively: Fexofenadine up to 360mg twice daily. [Guillén-Aguinaga et al.]
If maximum antihistamines are ineffective, montelukast 10mg ODN can be added.
If maximum antihistamines and montelukast are ineffective, trial with Famotidine 20mg twice daily.
If the patient has difficulty sleeping, 10mg hydroxyzine ON can be added.
If maximum antihistamines (including alternative antihistamine), and montelukast are ineffective, omalizumab (anti-IgE monoclonal antibody) should be considered by allergy team via MDT.
Failure of omalizumab necessitates consideration of immunosuppression, e.g. cyclosporine or tacrolimus
Please be aware that CSU may be confused with so-called, “urticarial vasculitis”, which can be distinguished by their long-lasting nature (>24 hours in a fixed location), often burning rather than pruritic, and bruising/hyperpigmentation is left on resolution. Skin biopsy is needed for diagnosis and these patients should be referred to the vasculitis team.

References

Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta-analysis. S. Guillén-Aguinaga et al. British Journal or dermatology. Volume 175, Issue 6. December 2016. Pages 1153-1165

Vaccine allergies

The Green Book is a useful resource for information about vaccinations, dosage, contra-indications and allergy to vaccines.

There is helpful information about use of seasonal influenza vaccination in patients with egg allergy. There is also information about coronavirus vaccinations in patients with prior allergies, and management of patients who react to these vaccinations.