Anaphylaxis, angioedema and allergy

Anaphylaxis

• Lifetime risk of 1-3%
• Most common causes
  • Beta-lactams and contrast greatest risk of death
  • Shellfish
  • Soybeans
  • Nuts
  • ASA
  • Bactrim
  • Hymenoptera stings
  • Latex

Clinical criteria (ASCIA)

• Acute onset illness with typical skin signs +
  • Respiratory/CVS/severe GI
• Acute onset hypotension/bronchospasm/airway obstruction where anaphylaxis is a possiblity

Definition (Clinical Criteria)

• 1. Urticaria, generalised itching or flushing, or oedema of lips/tongue/uvula or skin developing over minutes to hours with at least one of:
  • Respiratory distress or hypoxia OR
  • Hypotension or cardiovascular collapse OR
  • Associated symptoms of organ dysfunction (hypotonia, syncope, incontinence)
• 2. Two or more signs or symptoms that occur minutes to hours after allergen exposure:
  • Skin and/or mucosal involvement
  • Respiratory compromise
  • Hypotension or associated symptoms
  • Persistent GI cramps or vomiting
• 3. Consider if exposed to known allergen and develop hypotension

Pathophysiology

• IgE cross-linking with mast cell and basophil activation
• Histamine
  • Vasodilation, vascular permeability, HR, cardiac contraction and glandular secretion
• Prostaglandin D2
  • Bronchoconstrictor, pulmonary and coronary vasoconstrictor and peripheral vasodilator
• Leukotrienes
  • Bronchoconstriction, vascular permeability
• Platelet-activating factor
  • Potent bronchoconstrictor and vascular permeability
• TNFalpha
  • Activates neutrophils, enhances chemokine synthesis

Presentation

• The faster the reaction, the more severe
  • Usually within 5 minutes if provoking agent is parenteral
• Half of all fatalities occur in first hour
• Cardiovascular system involvement occurs most commonly and may be the sole manifestation
  • Classically initial bradycardia, then sinus tachycardia, hypotension and shock
• Small risk of recurrence due to delayed phase of mediator release, peaking at 8-11 hours after initial exposure and manifesting signs 3-4 hours after initial clinical manifestations have cleared
  • Mediated by cysteinyl leukotrienes
  • Clinically important incidence of 5-20% (ASCIA) or 5% (Tintinalli)

Diagnosis

• Clinical diagnosis
• Consider if 2 or more body systems involved
• DDx: Vasovagal, asthma, MI, arrhythmias, epiglottitis, seizures, angioedema, foreign body, carcinoid syndrome, vocal cord dysfunction
• Tryptase
  • Neutral protease of unknown function found only in mast cells
  • Poor sensitivity (1/3 have normal levels on ED arrival)
  • Serial levels can be helpful (at presentation, 2 hours and 24 hours to confirm baseline level and preceding rise at presentation)

Symptoms

Treatment

• ABC
• Airway security is first priority in severe anaphylaxis
  • Intubate early if angioedema 
• Decontamination
  • Gastric lavage for food allergens is not recommended
  • Remove stingers or topical agents
• Adrenaline
  • Increases mast cell cAMP levels to prevent further histamine release + improves myocardial contractility, systemic vascular resistance, heart rate and bronchial smooth muscle relaxation
  • IM 0.5mg q5-10min
  • If refractory, IV bolus 100mcg over 5-10 minutes
  • If refractory initiate adrenaline infusion at 1mcg/min and titrate to effect
• IV crystalloid
  • 10-20mL/kg boluses of N/S with assessment of response

Second-line therapy

• Corticosteroids
  • Evidence for clinical benefit is scant but also no evidence of harm
  • Ideally reserved for refractory bronchospasm
  • Hydrocortisone 250-500mg IV 
  • Dexamethasone preferred for those in whom fluid retention would be problematic
• Antihistamines
  • Clinical benefit unproven
  • Recommended in Tintinalli but NOT ASCIA
    • ASCIA states sedating antihistamines may mimic other signs of anaphylaxis
  • Diphenhydramine 25-50mcg IV slow infusion
  • In severe cases, H2-receptor blocker such as ranitidine also recommended
• Vasopressors
  • Adrenaline preferred but if dangerous arrhythmias can consider noradrenaline/metaraminol/vasopressin

Second-line therapy

• Bronchospasm therapy
  • Salbutamol MDI/neb
  • Ipratropium + IV MgSO4 if refractory
  • IV aminophylline is not recommended
  • Leukotriene receptor antagonists are not effective for anaphylaxis
• Glucagon
  • Use of beta-blockers is a risk factor for severe prolonged anaphylaxis
  • If on beta-blockers and refractory to adrenaline and fluids, IV glucagon 1mg q5min until hypotension resolves followed by an infusion
  • Nausea, vomiting, hypokalaemia, dizziness and hyperglycaemia may result

Second-line therapy

• ASCIA state steroids only recommended in acute setting if bronchospastic (not effective for shock apparently)
• ASCIA also recommends nebulized adrenaline 5mg for upper airway obstruction + intubation

Disposition and follow-up

• Admission to hospital required for 1-4%
• If refractory to therapy or intubation required, needs ICU admission
• After adrenaline, otherwise healthy patients who remain symptom-free after 4 hours can be safely discharged home
• Consider prolonged observation if severe reaction or on beta-blockers
• If live alone, live in rural area, have significant comorbidity (esp. asthma) or are elderly should be monitored for longer
• Anaphylaxis action plan and EpiPen education + script is mandatory
• Refer patients with severe or recurrent reactions to an allergist
• Consider medicalert bracelet
• Switch patients on beta-blocker to CCB for example

Who to admit for overnight obs?

• Severe or protracted anaphylaxis
• History of severe or protracted anaphylaxis
• History of asthma
• Concomitant illness
• Live alone or remotely
• Present in the evening

Anaphylactoid

• Direct histamine-releasing effect of drugs or other triggers
• Morphine specifically releases histamine in skin and is unlikely to cause bronchospasm
• Atracurium, vecuronium and propofol can cause histamine release in lungs leading to bronchospasm
• Widespread release with vancomycin

Urticaria

• Cutaneous reaction marked by acute onset of pruritic, erythemic wheals that migrate
• Erythema multiforme is more severe variation with target lesions
• May be allergic, viral
• Treatment
  • Supportive, symptomatic and attempts to identify trigger
  • H1-receptor antagonists +- corticosteroids
  • Adrenaline if severe
  • H2-receptor antagonists if severe, chronic or unresponsive
  • Cold compresses
• Refer to allergist if severe, recurrent or refractory case

Angioedema

• Similar to urticaria but with dermal oedema, generally involving the face, neck and distal extremities
• Tongue, lip and face swelling has airway compromise risk
• ACEi (0.1-0.7% of patients on these)
  • Bradykinin and substance P driven
  • Not responsive to adrenaline, antihistamine or corticosteroids as not IgE-mediated
  • Icartibant (bradykinin-2 antagonist) is effective and reduces time to resolution
  • C1-esterase inhibitor 1000IU IV
  • Ecallantide (kallikrein inhibitor) is not effective
  • Cease ACEi (do not use ARB though)
  • Most cases resolve in hours to days so observe for 12-24 hours and d/c once swelling subsided
  • Rebound swelling does not occur unless re-exposed to ACEi

Angioedema

• Hereditary angioedema
  • Autosomal dominant disorder due to C1 esterase inhibitor deficiency (low levels – Type 1 OR dysfunctional enzyme – Type 2)
  • 25% of cases are due to new mutations
  • Acute oedematous reactions involving upper respiratory, soft tissues of limbs and trunk or GI tract
  • Attacks last hours to days
  • Often precipitated by minor trauma
  • Screen for this by C4 level <30% of normal

Angioedema

• Hereditary angioedema
  • Treatment
    • C1 esterase inhibitor
    • Icatibant (bradykinin-2 receptor antagonist)
    • Ecallantide (kallikrein inhibitor)
    • FFP can be used if C1 esterase inhibitor is not available (2-3 U in most reports)
  • Prophylaxis
    • Stanozolol or danazol (androgens)

Food allergies

• Dairy products, eggs, nuts and shellfish are most common
• Symptoms
  • Swelling and itching of lips, mouth and pharynx
  • Nausea
  • Abdominal cramps
  • Vomiting
  • Diarrhoea
  • Angioedema, urticaria and anaphylaxis can occur
• Treatment
  • Antihistamines
  • Adrenaline/steroids if severe

Allergic drug reactions

• True hypersensitivity reactions account for <10% of adverse drug reactions
• Penicillin is most common cause (90% of all reported allergic drug reactions and 75% of fatal anaphylactic reactions)
  • <25% of patients who die of penicillin-induced anaphylaxis exhibited allergy during previous treatment with the drug
  • Parenteral penicillin administration is 2x more likely to cause fatal allergic reactions than oral preparations
  • Cross-reactivity with cephalosporins is around 10%
• Generalised reaction (like serum sickness) is very common, especially with bactrim and cefaclor)
• Sulfa allergic reactions to non-antibiotic sulfas is uncommon (heaps of drugs have sulfa moieties)
• Drug fever, lupus-like syndrome, skin eruptions and delayed contact dermatitis are all possible
• Treatment
  • Oral antihistamines and steroids
  • Drug cessation
  • Referral to allergy specialist if severe

Last Updated on October 28, 2020 by Andrew Crofton