Anaphylaxis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Dushka Riaz, MD

Anaphylaxis is an acute systemic Type I Hypersensitivity allergic reaction. Anaphylaxis occurs when a person is exposed to a trigger allergen that they have been previously sensitized to. Anaphylaxis can occur through ingestion, skin contact or injection. ^[1] The allergen causes a release of mast cells into the circulation. ^[2] It is marked by life threatening compromise of airway, breathing and circulation. ^[3] Common causes in children are usually food whereas in adults it is usually linked to medications and insect stings. ^[4] The mainstay of prevention is to avoid the allergen. ^[1] The mainstay of treatment is epinephrine. ^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Dushka Riaz, MD

The term comes from the Greek words ana (against) and phylaxis (protection).

Anaphylaxis was first discovered by Charles Richet and Paul Portier, who were French physiologists in 1913. ^[1] During their study of Physalia, Portugese man- o -war toxin, they began a series of experiments on a dog. They injected the toxin in the dog and repeated this days later. ^[2] They found an exaggerated immune response resulting in the dog experiencing collapse of the airway, breathing, and circulatory systems. ^[1] They named it anaphylaxis as they felt the phenomenon was the opposite of protection, or prophylaxis. ^[3] Richet was awarded a Noble Prize for his work in 1913. ^[4]

In the year 1937, Daniel Bovet discovered antihistamines, and cortisone was introduced in the year 1949. ^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Dushka Riaz, MD

Anaphylaxis may be classified into 2 subtypes/groups: Immunologic-IgE mediated and Immunologic-non-IgE mediated. ^[1]

The diagnostic criteria must have one of the three of the following: ^[2]

• 1. Acute onset of disruption of the skin or mucosal tissue with either reduced blood pressure or decreased perfusion and/or respiratory compromise.
• 2. Exposure to a likely allergen followed with two of the following: involvement of mucosal tissue, respiratory compromise, gastrointestinal disturbances, or reduced blood pressure
• 3. Reduced blood pressure after exposure to a known allergen

Anaphylaxis may be classified into two groups: ^[1]

• Immunologic-IgE: whose causes include food allergens, medications, latex, airborne allergens
• Immunologic-non-IgE: whose causes include IVIG, NSAIDS and aspirin

There are also three pattern classifications:

• Uniphasic which resolves in an hour
• Biphasic which includes recurrence even without repeated exposure ^[3]
• Protracted which can lasts for days ^[4]

Anaphylaxis can also be categorized according to the cause: ^[5]

• Anaphylaxis caused by food allergens
• Anaphylaxis caused by drug allergens
• Anaphylaxis caused by insect venom
• Anaphylaxis caused by physical factors
• Anaphylaxis caused by inhaled allergens
• Anaphylaxis caused by allergen contact
• Anaphylaxis caused by mast cell disorders

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Dushka Riaz, MD

The progression to anaphylaxis usually involves an IgE-mediated or non IgE-mediated response. It is a medical emergency that involves multiple systems. ^[1] The condition involves pulmonary, gastrointestinal, cardiovascular and integumentary systems and can lead to cardiorespiratory arrest. ^[2]

Anaphylaxis is usually caused by food, particularly peanuts, drugs, and insect venoms. ^{[3] [4]} There have also been cases of idiopathic anaphylaxis. ^{[5] [6]} Anaphylaxis arises from mast cell and basophil degranulation after repeated exposure to an antigen. This results in a type 1 hypersensitivity reaction. The IgE then crosslinks and aggregates with receptors resulting in the release of histamine, proteoglycans, and tryptase. This results in arachidonic acid metabolites being released with further consequences. The reaction as a whole leads to vasodilation, increase heart rate, bronchoconstriction, and hypoperfusion of vital organs. ^[1]

Specifically, histamine causes vasodilation and increased heart rate and permeability which ultimately leads to the hypoperfusion of various tissues. Prostaglandin D2 causes bronchoconstriction of both cardiac and pulmonary systems culminating in peripheral vasodilation and further hypoperfusion of tissues. Leukotrienes and platelet activation factor also contribute to vascular permeability, along with bronchoconstriction and airway remodeling. Finally, TNF-alpha activate neutrophils which increases the synthesis of chemokines. ^{[7] [1]}

Anaphylaxis can be divided into IgE-dependent and IgE-independent mechanisms. IgE levels are higher in those patients that have allergies. Once IgE binds to FcεRI on mast cells and basophils this releases histamine and other inflammatory mediators. On repeat exposure to the antigen, these IgE aggregates lead to anaphylaxis. ^[8] IgE levels are even used during the diagnosis of allergies to determine what allergens a patient is susceptible to. ^[9] Meanwhile, in IgE-independent reactions, IgG mechanisms were also found to lead to anaphylaxis, which has largely been studied in mice. A single episode of anaphylaxis may also be caused by simultaneous IgG and IgE-mediated pathways. ^[10]

Genes involved in the pathogenesis of anaphylaxis include:^{[11] [12] [13] [14] [15] [16] [17] [18] [19]}

• Polymorphisms in IL-10, IL-13, IL-4Rα are linked to anaphylaxis to drugs and latex.
• PAF-AH activity levels are correlated inversely with the severity of anaphylaxis.
• Variations in angiotensinogen MM genotype with low levels of angiotensin are linked with high rates of hymenoptera venom allergy.
• Patients with peanut allergies and low serum ACE levels are linked with high rates of pharyngeal edema.
• Activating mutation in c-KIT and D816V are associated with mastocytosis and hyperresponsivity of their mast cells with resulting increasing severity of anaphylaxis rates.
• Anaphylaxis occurs more commonly in women, though the mechanism is not clear.

Conditions associated with anaphylaxis include the following and are associated with poor prognosis: ^{[20] [21]}

• Asthma
• Cardiovascular disease
• Antihypertensive medication use

On gross pathology, basophil and mast cell degranulation are characteristic findings of anaphylaxis. ^[1]

On microscopic histopathological analysis, upper airways showing eosinophils due to edema are characteristic findings of anaphylaxis. Tissue sections can also show tryptase, which is an enzyme specific to mast cells. ^[22]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Vidit Bhargava, M.B.B.S [2]Soumya Sachdeva, , Associate Editor(s)-in-Chief: Dushka Riaz, MD

Anaphylaxis can have IgE-mediated, non IgE-mediated and nonimmunologic triggers. IgE mediated allergens include reactions to food, medications and animal dander. Non-IgE mediated reactions can be caused by IVIG, biologic agents and NSAIDs. Nonimmunologic triggers to anaphylaxis include radiocontrast media, opiates, and changes in temperature. ^[1] Adult cases are more commonly caused by medications and insect stings while children are more triggered by food. ^[2]

Anaphylaxis is itself a life-threatening condition caused by various allergens. ^[1]

Anaphylaxis can occur in response to any allergen. Common causes include: ^{[3] [4] [5] [6] [7] [8] [9] [10] [11]}

• Drug allergies (acetaminophen, penicillins, Prednisolone, cephalosporins, amphotericin B, nitrofurantoin, quinolones)

• Food allergies (peanuts, milk, eggs, seafood, nuts, grains, beans, gelatin in capsules)

• Insect bites/stings (yellow jacket, yellow and baldfaced hornets, paper wasp, honey bee, imported fire ants)

• Nonpollen allergen extracts (dust mites, dander of cats, dogs, horses and laboratory animals)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Dushka Riaz, MD

Anaphylaxis must be differentiated from carcinoid syndrome, globus hystericus, hereditary angioedema, pheochromocytoma, pulmonary embolism, scombroid intoxication, systemic mastocytosis, vagal reactions, irritable bowel syndrome, Crohn’s disease, malignant neoplasm of the small intestine, benign cutaneous flushing, asthma exacerbation, and medullary thyroid carcinoma. ^[1]

First administration of the following drugs or agents:

• Aspirin
• Contrast media (first contact)
• Pentamidine (first contact)
• Polymyxin (first contact)

Conditions that may mimic anaphylaxis include the following:

• Carcinoid Syndrome
• Globus hystericus
• Hereditary angioedema
• Pheochromocytoma
• Pulmonary Embolism
• Scombroid intoxication
• Systemic Mastocytosis
• Vagal reactions

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Dushka Riaz, MD

• In 2006, the lifetime prevalence of Anaphylaxis was estimated to be 0.05% to 2% in the United States. However it is believed that this is an underestimation because the disease is underdiagnosed. ^[1]

• The mortality rate of Anaphylaxis is approximately 186 to 225 deaths/year. ^[2]

• Patients of all age groups may develop anaphylaxis, however, children and adolescents account for the majority of cases.^[3]

• There is no racial predilection to anaphylaxis.

• Anaphylaxis affects men and women equally with more women being admitted to the hospital for the disease. ^[1]

• There is no regional predilection to anaphylaxis.

An estimated 1.24% to 16.8% of the United States population is considered at risk for developing anaphylaxis if they are exposed to one or more allergens. Anaphylaxis results in fewer than 1,000 deaths per year in the U.S and the most common presentation is cardiovascular collapse ^{[4] [5]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Dushka Riaz, MD

Common risk factors in the development of anaphylaxis include those related to age, sex, exposure, and other comorbid conditions such as asthma. Delayed use of epinephrine to treat anaphylaxis places patients at increased risk of being hospitalized whereas timely use decreases this risk. ^[1] Patients that have features of increased risk towards anaphylaxis should be advised to carry auto-injectable epinephrine. ^[2]

Common risk factors in the development of anaphylaxis include age, sex, geography, history of asthma, atopic history, and interruption of medication.^{[3] [4] [5] [6] [7]}

• Common risk factors in the development of anaphylaxis include:
  • Age, with more incidence in boys younger than 15 and women older than 15 years old.
  • Sex, with more incidence in women exposed to latex and aspirin; men have more incidence with venom stings.
  • Geography, the incidence of anaphylaxis is higher in Northern areas.
  • History of asthma places patients at higher risk to develop anaphylaxis.
  • History of atopy increases the risk of anaphylaxis.
  • Interruption of medications after desensitization can increase the risk of anaphylaxis.

• Less common risk factors in the development of anaphylaxis include:
  • Comorbid ischemic dilated cardiomyopathy or coronary arterial disease
  • Antihypertensive medication use
  • Tricyclic antidepressant medication use
  • Monoamine oxidase inhibitor medication use
  • Mastocytosis
  • Chronic Obstructive Pulmonary Disease
  • Upper Respiratory tract infection
  • Emotional stress
  • Fever

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Dushka Riaz, MD

Common complications of anaphylaxis include airway blockage, cardiac arrest, respiratory arrest, and shock. Prognosis is generally good with prompt diagnosis and treatment. It is important to follow up with an allergist to determine the exact cause of the anaphylaxis and advise the patient to avoid it in the future. ^[1] The main cause of mortality is cardiovascular compromise or airway compromise and is more common in patients with asthma. ^[2]

• The symptoms of anaphylaxis usually develop within seconds with rapid evolution. It usually carries an unpredictable course and can resolve as quickly as it began. If left untreated, anaphylaxis can progress to respiratory or cardiovascular compromise. ^{[3] [4]}

Possible complications include: ^[5]

• Airway blockage
• Cardiac arrest (no effective heartbeat)
• Respiratory arrest (no breathing)
• Shock

Anaphylaxis can be fatal without prompt treatment. symptoms generally resolve quickly with prompt treatment. Depending on the availability of epinephrine treatment, the prognosis may vary. ^[5]

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