Definition of anaphylaxis

Anaphylaxis is a multisystem reaction to allergen exposure. Although the term was coined in 1902, pervasive inconsistencies in its application have made interpretation of the literature difficult. In an effort to standardize research and treatment of anaphylaxis, a joint panel from the American Academy of Allergy Asthma and Immunology; the American College of Allergy, Asthma and Immunology; and the Joint Council of Allergy, Asthma and Immunology agreed on a consensus definition of anaphylaxis in 2006 and recently revised it. They define anaphylaxis as one of the following:

• 1.
  

  The acute onset of a reaction (minutes to hours), with involvement of the skin, mucosal tissue, or both, and at least one of the following:

  
  
  
  
  • 
    

    Respiratory compromise

    
    
  • 
    

    Reduced blood pressure or symptoms of end-organ dysfunction

  
  
  
  
• 2.
  

  Two or more of the following that occur rapidly after exposure to a likely allergen for that patient

  
  
  
  
  • 
    

    Involvement of the skin/mucosal tissue

    
    
  • 
    

    Respiratory compromise

    
    
  • 
    

    Reduced blood pressure or associated symptoms

    
    
  • 
    

    Persistent gastrointestinal (GI) symptoms

  
  
  
  
• 3.
  

  Reduced blood pressure after exposure to a known allergen.

Although this definition is cumbersome, it highlights the fact that anaphylaxis is not always characterized by severe respiratory and cardiovascular compromise; persistent abdominal pain and urticaria after ingestion of a likely allergen (for that patient) also meet the definition of anaphylaxis. Generally, anaphylaxis has been understood as an IgE-mediated reaction, although the World Allergy Organization has recommended that non-IgE–mediated anaphylaxis-type reactions be included under the term. So far, US consensus panels have rejected that suggestion, and in this review, anaphylaxis refers to an IgE-mediated syndrome.

Pathophysiology of anaphylaxis

The initiating event in an anaphylactic episode is the association between the allergen and membrane-bound IgE on mast cells and basophils. This association leads to aggregation of the high-affinity IgE receptor, triggering an intracellular signaling cascade that ultimately leads to calcium influx and degranulation of the cell. Activation of mast cells and basophils causes release of preformed mediators of inflammation (histamine, tryptase, carboxypeptidase A, proteoglycans, and some cytokines) and newly generated mediators (leukotrienes, cytokines including tumor necrosis factor [TNF]-α, and platelet-activating factor [PAF]). Ultimately, these mediators cause the characteristic clinical features of anaphylaxis, including vasodilation, angioedema, bronchoconstriction, and increased mucus production.

Histamine, one of the preformed mediators released by mast cells and basophils, can recapitulate most of the signs and symptoms of anaphylaxis when administered intravenously to humans and laboratory animals. Histamine acts through H1 and H2 receptors on multiple organ systems. Its effects on the vascular bed include release of nitric oxide by endothelial cells (H1 receptors) and direct relaxation of smooth muscle (H2 receptors). In the lung, bronchoconstriction is mediated by H1 receptors, whereas stimulation of both H1 and H2 receptors causes increased production of mucus. Histamine increases cardiac oxygen demand indirectly by peripheral vasodilation and via direct effects on the heart, including increased contractility, shortened depolarization, and increased heart rate. Histamine can also cause coronary artery vasospasm through the H1 receptor.

Other mediators of anaphylaxis include leukotrienes and other products of arachidonic acid metabolism, including prostaglandins; PAF (discussed in more detail later); the neutral proteases such as tryptase and chymase; the proteoglycans, including heparin; and various chemokines. These mediators recruit inflammatory cells and activate complement cascades, among other mechanisms.

Over the past 5 years, several studies have highlighted the role of PAF in the propagation of anaphylaxis. PAF is a preformed mediator of anaphylaxis released by mast cells, monocytes, and tissue macrophages. It is degraded by PAF-acetylhydrolase. In a seminal article published in 2008, Vadas and colleagues measured PAF and PAF-acetylhydrolase in patients with varying gradations of anaphylaxis severity. They found significant correlation between PAF levels and the severity of anaphylaxis; all subjects with severe anaphylaxis had elevated PAF levels. In addition, levels of PAF-acetylhydrolase were inversely correlated with the severity of anaphylaxis. Subsequently, Arias and colleagues showed that blocking PAF prevents severe anaphylactic reactions, and, when combined with antihistamines, abolishes nearly all signs of anaphylaxis. Further, Kajiwara and colleagues demonstrated that PAF, by itself, was capable of activating mast cells in the lung and peripheral blood but not in the skin. The role of PAF-acetylhydrolase deficiency as a risk factor for severe allergic reactions is an area of active exploration.

Pathophysiology of anaphylaxis

The initiating event in an anaphylactic episode is the association between the allergen and membrane-bound IgE on mast cells and basophils. This association leads to aggregation of the high-affinity IgE receptor, triggering an intracellular signaling cascade that ultimately leads to calcium influx and degranulation of the cell. Activation of mast cells and basophils causes release of preformed mediators of inflammation (histamine, tryptase, carboxypeptidase A, proteoglycans, and some cytokines) and newly generated mediators (leukotrienes, cytokines including tumor necrosis factor [TNF]-α, and platelet-activating factor [PAF]). Ultimately, these mediators cause the characteristic clinical features of anaphylaxis, including vasodilation, angioedema, bronchoconstriction, and increased mucus production.

Histamine, one of the preformed mediators released by mast cells and basophils, can recapitulate most of the signs and symptoms of anaphylaxis when administered intravenously to humans and laboratory animals. Histamine acts through H1 and H2 receptors on multiple organ systems. Its effects on the vascular bed include release of nitric oxide by endothelial cells (H1 receptors) and direct relaxation of smooth muscle (H2 receptors). In the lung, bronchoconstriction is mediated by H1 receptors, whereas stimulation of both H1 and H2 receptors causes increased production of mucus. Histamine increases cardiac oxygen demand indirectly by peripheral vasodilation and via direct effects on the heart, including increased contractility, shortened depolarization, and increased heart rate. Histamine can also cause coronary artery vasospasm through the H1 receptor.

Other mediators of anaphylaxis include leukotrienes and other products of arachidonic acid metabolism, including prostaglandins; PAF (discussed in more detail later); the neutral proteases such as tryptase and chymase; the proteoglycans, including heparin; and various chemokines. These mediators recruit inflammatory cells and activate complement cascades, among other mechanisms.

Over the past 5 years, several studies have highlighted the role of PAF in the propagation of anaphylaxis. PAF is a preformed mediator of anaphylaxis released by mast cells, monocytes, and tissue macrophages. It is degraded by PAF-acetylhydrolase. In a seminal article published in 2008, Vadas and colleagues measured PAF and PAF-acetylhydrolase in patients with varying gradations of anaphylaxis severity. They found significant correlation between PAF levels and the severity of anaphylaxis; all subjects with severe anaphylaxis had elevated PAF levels. In addition, levels of PAF-acetylhydrolase were inversely correlated with the severity of anaphylaxis. Subsequently, Arias and colleagues showed that blocking PAF prevents severe anaphylactic reactions, and, when combined with antihistamines, abolishes nearly all signs of anaphylaxis. Further, Kajiwara and colleagues demonstrated that PAF, by itself, was capable of activating mast cells in the lung and peripheral blood but not in the skin. The role of PAF-acetylhydrolase deficiency as a risk factor for severe allergic reactions is an area of active exploration.

Diagnosis of anaphylaxis

There are 2 components to the diagnosis of food-induced anaphylaxis. The first is the recognition of an anaphylactic event, and the second is the identification of the etiologic agent.

Atypical food-induced anaphylaxis

Two unusual types of food-induced anaphylaxis, food-dependent exercise-induced anaphylaxis and carbohydrate-induced anaphylaxis, merit special comment. Food-dependent exercise-induced anaphylaxis is a rare cause of anaphylaxis. In this syndrome, patients tolerate both the causative food and exercise in isolation, but not together. Typically, this syndrome presents in adolescence or in individuals in the 20s, but it can occur at any age. The time between consumption of the food and onset of symptoms is frequently longer than in other kinds of food-induced anaphylaxis, as reactions have been reported hours after eating the food. Usually, symptoms begin within 30 minutes of the start of exercise, but can occur at any time during the workout and with any intensity of exercise. The initial stage usually consists of cutaneous signs and fatigue, followed by more generalized symptoms.

The most common food to trigger food-dependent exercise-induced anaphylaxis is wheat, followed by other grains, nuts, and seafood. Skin prick testing and food-specific IgE can help confirm the diagnosis, although the size of the skin test or level of food-specific IgE is usually lower than that found in other types of food allergy. The mechanism of exercise-induced anaphylaxis is thought to be increased permeability of the gut to undigested allergens, although this is only speculative. Exercise-induced anaphylaxis can be confused with cholinergic urticaria, in which hives occur with heating. Cholinergic urticaria is not typically accompanied by the systemic symptoms that are characteristic of exercise-induced anaphylaxis, and symptoms can be reproduced by passive heating. The current recommendation for prevention of food-dependent exercise-induced anaphylaxis is to either completely avoid the food or to wait at least 6 hours between food ingestion and exercise. Additional important measures are for patients to carry self-injectable epinephrine and exercise with a partner who is aware of the condition and able to assist.

Another unusual type of anaphylaxis to food has been called delayed anaphylaxis to red meat or carbohydrate-induced anaphylaxis. This condition has recently been reported in patients living in the southeastern United States and Australia who presented with anaphylaxis 3 to 6 hours after ingesting red meat. Commins and colleagues found that these patients had IgE to a carbohydrate found on mammalian serum albumin called galactose-α-1,3-galactose (α-gal). The condition usually begins in adulthood and seems to have a particular geographic specificity. An intriguing hypothesis to explain the age and geographic distribution of α-gal sensitization is that the bite of a tick endemic to this geographic region sensitizes people to the α-gal. Indeed, a history of tick bite is more common in patients with sensitivity to α-gal. General practitioners should be aware of this unusual type of anaphylaxis and refer patients to allergists for evaluation if it is suspected.

Severe and fatal anaphylaxis

Food-allergy–induced fatalities remain rare, although fear of fatal reactions contributes to the anxiety that exists in families with a food-allergic child. Since Yunginger and colleagues first described a series of deaths from food-induced anaphylaxis in 1998, the most important risk factor for a severe reaction remains a history of asthma. In the series published thus far, the prevalence of a positive history for asthma in fatal reactions has approached 100%. In addition to asthma, several other features of a food allergen exposure seem to convey particular risk. Adolescence is the age at greatest risk for a fatal reaction, from increased reactivity or, more likely, because of increased risk-taking behavior. Peanuts are the most common cause of fatal reactions, causing 50% to 60% of fatal reactions. Tree nuts account for another 15% to 30% of fatal reactions. In 2 reports from the United States and Great Britain attempting to account for as many food-related fatalities as possible between 2001 and 2006 (United States) and 1999 and 2006 (Great Britain), milk emerged as the next most common cause, accounting for 13% of deaths in each series. Shellfish, fish, eggs, sesame, and selected fruits and vegetables account for most of the remaining causes.

Attempts to find other markers that prospectively identify patients at risk for severe reactions have been largely unsuccessful. Although some have found correlations between food-specific IgE titers and/or skin prick test size and the magnitude of clinical reactivity, most have found them to be poorly predictive of reaction severity with food challenge or accidental exposure. This is, perhaps, not surprising, given that the correlation between reaction severity in the clinic and in the community is itself weak ( r ² = 0.37), likely because of variable exposure doses. Recent studies of immunotherapy for food allergy offer an interesting opportunity to explore risk factors for reaction at a given dose. Exercise, concurrent illness, and menstrual status were identified as risk factors for unexpected or more severe reactions to a given dose. These findings may not extend to community-based reactions, but it is likely that incident-specific factors, such as those mentioned earlier, and concurrent intake of alcohol are the most important predictors of severe reactions.

Differential diagnosis of anaphylaxis

The differential diagnosis of anaphylaxis includes other illnesses that cause acute respiratory distress, syncope, rash, and/or GI distress. In children, vocal cord dysfunction, panic attacks, and vasovagal reactions (also known as vasodepressor reactions) deserve particular note. Vocal cord dysfunction is caused by abnormal adduction of the vocal cords during inspiration. It can coexist with asthma, and the wheezing and coughing can mimic anaphylaxis. Treatment is speech therapy. Signs and symptoms found in vasovagal reactions, including hypotension, nausea, vomiting, and diaphoresis can mimic anaphylaxis, but these reactions lack the typical skin manifestations found in anaphylaxis. In contrast to anaphylaxis, vasovagal reactions are characterized by bradycardia, whereas anaphylaxis is usually, but not always, accompanied by tachycardia. Other causes of flushing, including the red man syndrome from vancomycin, should be considered in the differential.

Miscellaneous food-related conditions that can be confused with anaphylaxis include scombroid poisoning, which mimics anaphylaxis closely, as it is caused by consumption of histamine itself, and monosodium glutamate-related flushing, which is not an IgE-mediated condition. Food protein–induced enterocolitis syndrome (FPIES) is a non-IgE–mediated disease presenting in infancy. Acute reactions usually include profound vomiting, leading to dehydration, lethargy, and hypotension, starting hours after the food is ingested. Awareness of this condition is important, as is the understanding that a negative skin prick test result or food-specific IgE does not rule it out.