Anaphylaxis: Brief Review

Author: V. Dimov, M.D., Allergist/Immunologist, Cleveland Clinic
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU


Figure 1. Mind map diagram of anaphylaxis (click to enlarge the image).

Definition of anaphylaxis

Anaphylaxis was originally described by Portier and Richet in 1902 when the second vaccinating dose of sea anemone toxin caused a dog's death. The response was the opposite of prophylaxis and thus was referred to as anaphylaxis, i.e. "without protection". Anaphylaxis is a severe systemic allergic reaction but there is no universally accepted definition. A good working definition is that anaphylaxis affects more than one organ system, most commonly, skin, respiratory, cardiovascular, and GI systems.

Impact of anaphylaxis

There are 100,000 episodes of anaphylaxis in the U.S. per year, of which almost 1% are fatal (0.65-2%). On average, severe anaphylaxis affects at least 1-3 persons per 10,000 population, and 1-15% of the U.S. population are at risk. An eidemiologic analysis evaluated 464 patients who were hospitalized in Florida for anaphylaxis in 2001. Hospital mortality rate was 0.86%. Median length of stay was 1 day. Median total charges were about $ 5,000. Asthmatics had an increased risk of receiving intubation and mechanical ventilation.

Anaphylaxis is common (1 in 20 adults), 50% never received epineprine, the majority have life-threatening reactions. Anaphylaxis represents a huge opportunity for clinical improvement (Wood, JACI, 2014).

The most common causes of death in anaphylaxis are shock and laryngeal edema. Asthma is a risk factor for fatal outcomes.

Mechanism of anaphylaxis

Anaphylaxis is a type I reaction in the Gell and Goombs classification of hypersensitivity remembered by the mnemonic ACID:

Anaphylaxis, angioedema, asthma, type I
Cytotoxic, antibody-mediated, type II, e.g AIHA, ITP, Graves' disease
Immune complex disease (CIC), type III, e.g. GN, serum sickness
Delayed, cell-mediated, type IV, e.g. contact dermatitis

An allergen reacts with specific IgE antibodies, bound to Fc receptors on mast cells and basophils. This leads to activation of the mast cells and release of mediators responsible for the clinical features of anaphylaxis (BMJ figure).

Rapid release of mediators in anaphylaxis causes the following events remembered by the mnemonic LESS:

Leakage (capilary) --> Urticaria, Angioedema, Laryngeal edema, Hypotension
Edema (mucosal) --> Laryngeal edema, Rhinitis, Wheezing
Smooth muscle contraction --> Wheezing, Abdominal pain
Shock

Increased vascular permeability (capilary leakage) can cause a shift of 50% of vascular volume to the extravascular space within 10 minutes, therefore leading to hypotension and shock. Epinephrine should be administered as early as possible to prevent this fluid shift and shock.

Etiology of anaphylaxis

Foods and insect venom are the 2 most common causes of anaphylaxis. Allergen immunotherapy (desensitization) may also induce anaphylaxis. A total of 46 deaths due to immunotherapy and skin testing were reported from 1945-1987.

Food ingestion is the cause of anaphylaxis in 36% of cases; a medication, allergy immunotherapy, or a diagnostic agent is the cause in 17% of cases; and insect stings are the cause in 15% of cases, 32% are idiopathic.

The common causes of anaphylaxis are remembered by the mneminic FIDL:

Foods - tree nuts, shellfish, 36%
Insect stings - Hymenoptera (bee and wasp), 15%
Drugs - beta-lactams, NSAIDs, 17%
Latex rubber

Anaphylaxis to penicillin (PCN) occurs in 1-5 cases per 10,000 patient treatment courses, with fatalities in 1 case per 50,000-100,000 courses. Insect stings cause 25-50 deaths per year in the U.S.

The largest study of childhood anaphylaxis (as of 2008) included 117 children. Home was the most common setting (48%) and food (85%) the most common trigger. The median age of presentation was 2.4 years. Peanut (18%) and cashew nut (13%) were the most common cause of anaphylaxis.

The 8 top allergens which account for 90 % of all food allergies are remembered by the mnemonic TEMPS WFS:

Tree nuts (almonds, cashews, walnuts)
Egg white (not egg yolk)
Milk
Peanuts
Shellfish (crab, lobster, shrimp)
Wheat
Fish (bass, cod, flounder)
Soy

The most common drugs causing anaphylaxis can be remembered by the mnemonic AAA CAN

Antibiotics (especially penicillin)
Anesthetic drugs, IV
ASA (aspirin)

Contrast media for radiologic studies, IV
Analgesic opioids
NSAIDs

Risk factors for anaphylaxis due to immunotherapy can be remembered by the mnemonic OH BEA:

Observation - insufficient, following injection
High allergen dose

Beta-blockers
Errors in administration
Asthma, poorly controlled

Clinical Features of anaphylaxis

The clinical features of anaphylaxis can be remembered by the mnemonic S ECG:

Skin, 90%
Expiratory wheezing and other respiratory symptoms, 70%
Cardiovascular, 40%
GI and oral, 25%

Skin: Eythema, Pruritus, Urticaria, Angioedema.
Respiratory: Laryngeal edema, Wheezing, Rhinitis, Conjunctivitis, Itching of palate or external auditory meatus.
Cardiovascular: Palpitations, Sense of impending doom, Fainting, lightheadedness, Collapse, Loss of consciousness.
GI and oral: N/V/D, abdominal pain.

Specific features will often depend on route of allergen entry, for example, insect stings, intravenous drugs can cause cardiovascular problems, especially hypotension and shock. Foods which are absorbed transmucosally can cause lip, facial, and laryngeal edema.

Typically, symptom onset occurs within minutes after exposure and progression is rapid.

Latex rubber anaphylaxis is somewhat unusual because it develops more slowly (30 minutes) as the allergen has to be absorbed through the skin or mucosa.

Diagnosis of anaphylaxis

Anaphylaxis is a clinical diagnosis based on the history of acute exposure to an allergen followed by the typical systemic manifestations. Laboratory studies are not usually required.

Laboratory tests

- Histamine rises within 5-10 minutes and peaks at 30-60 minutes

- Tryptase peaks at 60-90 minutes and persist for 6 hours

- 24-hour urinary histamine metabolites are increased for up to 24 hours

Serum tryptase levels may not be reliable in food-induced anaphylaxis.

Platelet-Activating Factor (PAF) may become the "BNP" of anaphylaxis in the future -- a laboratory test which helps in diagnosis. The analogy between PAF and BNP also comes from the fact that both tests help stratify the severity of the disease. The higher then BNP, the more severe the CHF exacerbation is. The same rule applies to PAF.

According to a study published in the NEJM, serum PAF levels were directly correlated with the severity of anaphylaxis. The proportion of subjects with elevated PAF levels increased from 4% in the control groups to 20% in the group with grade 1 anaphylaxis, 71% in the group with grade 2 anaphylaxis, and 100% in the group with grade 3 anaphylaxis.

Management of anaphylaxis

A recent study in the Annals of Allergy, Asthma and Immunology reported on development reported on development of the acronym SAFE, a mnemonic to remind physicians of the 4 action steps for anaphylaxis treatment:

Seek support
Allergen identification and avoidance
Follow-up for specialty care
Epinephrine for emergencies

Drugs used for management of anaphylaxis are remembered by the mnemonic EASI:

Epinephrine IM
Antihistamines PO, IM
Steroids PO, IM, IV
Inhaled b2-agonists, if wheezing. IV fluids if hypotension.

First-line therapy for anaphylaxis is epineprhrine (adrenaline) administered I.M. and it should be given as soon as the condition is recognized. Supplementary therapies include IVF, nebulized bronchodilators, antihistamines and corticosteroids (mnemonic EASI).

Epinephrine should not be given IV except under special circumstances such as profound shock or during anaesthesia. Myocardial infarction has rarely been reported in association with the use of epinephrine. Beta-blockers may increase the severity of an anaphylactic reaction and may antagonize the effect of epinephrine. Use of beta-blockers is not a contraindication to administering epinephrine. Glucagon IM can be administered in patients who take beta-blockers and have developed anaphylaxis.

Bi-phasic anaphylactic reactions have been described but are rare. Administration of steroids should minimize the risk of late relapse. The new guidelines require the prescription of 2 doses of self-injectable epinephrine to all patients (EpiPen 2-Pak).

Table: Management of acute anaphylaxis in the healthcare setting (adapted from Kemp et al. 2008).

Immediate intervention

- Assessment of airway, breathing, circulation and adequacy of mentation

- Administer adrenaline intramuscularly every 5–15 min, in appropriate doses, as necessary, depending on the presenting signs and symptoms of anaphylaxis, to control signs and symptoms and prevent progression to more severe symptoms such as respiratory distress, hypotension, shock and unconsciousness. Epinephrine (adrenaline) is the first-line the treatment of anaphylaxis. Adult intramuscular dose is 0.3 to 0.5 ml of 1:1,000 concentration. This should be given in the lateral aspect of the thigh by intramuscular injection. The dose can be repeated every 5 to 15 minutes, depending upon the response, for 3-4 doses. The same is true for children except the dose is 0.01 mg per kg (AAAAI Ask the Expert, 2012).

- Possibly appropriate, subsequent measures depending on response to adrenaline:

- Place patient in recumbent position and elevate lower extremities

- Establish and maintain airway

- Administer oxygen

- Establish venous access

- Normal saline intravenously for fluid replacement

Specific measures to consider after epinephrine injections, where appropriate:

Consider adrenaline infusion

Consider H1 and H2 antihistamines

Consider nebulized β2 agonist (e.g. albuterol [salbutamol]) for bronchospasm resistant to epinephrine

Consider systemic corticosteroids

Consider vasopressor (e.g. dopamine)

Consider glucagon for patient taking β-blocker

Consider atropine for symptomatic bradycardia

Consider transportation to an emergency department or an intensive care facility

For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged resuscitation efforts are encouraged, if necessary

Prevention of anaphylaxis

1. Avoid exposure.

2. Refer to an allergist. Allergy assessment is mandatory in all patients with a history of anaphylaxis to identify and avoid the allergen to prevent its recurrence.

3. Preloaded EpiPen syringes for self treatment of anaphylaxis. Self-injectable epinephrine (adrenaline) should be prescribed in most patients with a history of anaphylaxis. According to a study published in JACI, there were 1,5 million EpiPen prescriptions filled in 2004 with an average of 5.7 EpiPens prescribed per 1000 persons. Massachusetts had the highest number of prescriptions per 1000 persons (11.8), Hawaii had the lowest (2.7). Overall, New England states clearly lead the group with 8-12 EpiPens prescribed per 1000 persons, whereas the southern states had only 3. Authors suggest that the relative lack of sun exposure and vitamin D status may lead to higher incidence of anaphylaxis in the northern states which could explain this strong north-south "gradient."

Patients may be advised to wear a Medic-Alert bracelet with a warning regarding anaphylaxis towards a specific allergen.

References

Anaphylaxis guidelines by World Allergy Organization. JACI, 2011.
Anaphylaxis: Recent advances in assessment and treatment. JACI, Volume 124, Issue 4, Pages 625-636 (October 2009).

What Is Anaphylaxis? David B.K. Golden, MD. Current Opinion in Allergy and Clinical Immunology, Medscape, 09/2007.
Hospitalizations for Anaphylaxis in Florida: Epidemiologic Analysis of a Population-Based Dataset. Int Arch Allergy Immunol. 2007 May 25;144(2):128-136
Clinical review: ABC of allergies, Anaphylaxis. Pamela W Ewan. BMJ 1998;316:1442-1445.
Will Platelet-Activating Factor (PAF) be the "BNP" of Anaphylaxis? Allergy Notes, 01/2008.
Anaphylaxis articles from Allergy Notes.
How to Use EpiPen (Epinephrine) Auto-Injector. Allergy Notes.
Position paper: Management of anaphylaxis in childhood. EAACI Task Force on Anaphylaxis in Children. Allergy. 2007 Jun 21.
Anaphylactic Shock Due to Bee Sting. V. Dimov. Allergy Cases.
Anaphylaxis. Allergy Society of South Africa.
Anaphylaxis. eMedicine, 2005.
Paediatric anaphylaxis: a 5 year retrospective review. de Silva IL, Mehr SS, Tey D, Tang ML. Allergy. 2008 Aug;63(8):1071-6.
Anaphylaxis: diagnosis and management. Simon G A Brown, Raymond J Mullins and Michael S Gold. MJA 2006; 185 (5): 283-289.
Anaphylaxis in the Emergency Department: A Paediatric Perspective. Medscape, 11/2008.

What are the ‘ideal’ features of an adrenaline (epinephrine) auto-injector in the treatment of anaphylaxis? http://goo.gl/lxCh

Figure: Design overview of currently available auto-injectors for emergency self-administration of adrenaline in the treatment of anaphylaxis.

Related reading

Medicine in Stamps: Charles Richet (1850–1935): discoverer of anaphylaxis
History of Allergy: 1902, Charles Richet and Paul Portier invented the word 'anaphylaxis' 

Published: 09/08/2007
Updated: 06/22/2012