**3. Pathophysiology**

Anaphylaxis is caused by massive release of biochemical mediators from mast cell and basophils. Mast cells activation occurs mainly via antigen crosslinking of IgE bound to FcεRI receptors on cell membranes. However, other membrane receptors can activate mast cells as well or potentiate IgE activation [21]. The multiple activation pathways allow for immunologic (e.g. IgE mediated) and/or nonimmunologic activation (e.g. drug directly interacting with receptors) (**Figure 1**: mechanisms of mast cell degranulation). Some antigens may mediate effects via several mechanisms simultaneously (e.g. vespid venom, NSAIDs, opiates). In non-IgE mediated anaphylaxis, symptoms can occur on first exposure to an antigen as prior exposure and sensitization is not required.

Reproduced from Spoerl et al. [22] in agreement with publishing under terms of the Creative Commons Attribution (CC BY) license.

#### **3.1 Triggers and cell activation**

In IgE mediated anaphylaxis, an immunogen cross links membrane bound IgE in previously sensitized mast cell. Immunogens are typically large foreign proteins

**81**

*3.1.1 Food*

**Figure 1.**

carrots, and apples [25].

exposure [26].

*3.1.2 Venom*

*Anaphylactic Shock*

*DOI: http://dx.doi.org/10.5772/intechopen.88284*

with multiple epitope binding sites (e.g. proteins in insect venom and certain foods) [23]. Antigens that are too small to cross link IgE (e.g. penicillin) must first bind to larger carrier molecules in order to elicit an immune response. Common triggers of IgE-mediated anaphylaxis include various food, venom and medications are summarized in **Table 1**: IgE-dependent triggers and discussed in more detail below.

*Mechanisms of mast cell degranulation. Abbreviations: RCM, radiocontrast media; TLR. Toll-like receptor; SCF, stem cell factor; FcεRI, high affinity IgE receptor; FcγR, IgG receptor; TCR, T-cell receptor; NMBA, neuromuscular blocking agent; PAF, platelet activating factor; MHC, major histocompatibility complex.*

The most common foods causing anaphylaxis varies by region, in North America

Most cases of anaphylaxis due to food occurs in children or those with known food allergies, and fatal cases are rare [7, 8, 10]. When fatal, the cause of death is more often due to respiratory arrest, although shock can occur as well. Arrest occurs later compared to medication or venom, typically occurring 25–35 min after

Stinging insects belonging to the order Hymenoptera produce venoms that can cause anaphylaxis. The important insects from this order include bees, vespids (wasps, yellow jackets, hornets) and stinging ants [27]. Vespid venom additionally activates complement in an IgE independent mechanism, which may potentiate anaphylaxis [28]. In addition to hymenoptera venom, bites from rattlesnakes [29],

the most common food allergies includes milk, egg, peanuts, tree nuts, fish, shellfish, wheat, soy, and sesame [24]. Allergenic proteins have been identified for these common causes as well as in rice, barley, buckwheat, mustard, celery, potato,

### *Anaphylactic Shock DOI: http://dx.doi.org/10.5772/intechopen.88284*

#### **Figure 1.**

*Clinical Management of Shock - The Science and Art of Physiological Restoration*

includes reactions previously categorized as 'anaphylactoid reactions'.

Anaphylaxis is typically taught as Gell-Combs classification type 1 hypersensitivity, that is IgE mediated. However, the World Allergy Organization (WAO) proposed a new expanded definition of anaphylaxis *'a severe, life-threatening generalized or systemic hypersensitivity reaction*' [3]. This new definition of anaphylaxis now

End manifestation of anaphylaxis, occurs when there is inadequate tissue

Studies have estimated that the incidence of anaphylaxis is between 0.05 and 2.0% of the population [4], although the actual incidence is not clear. Issues previously identified with epidemiologic studies include variations in definitions, under reporting of anaphylaxis, and unclear use of incidence and prevalence of disease [5]. Although the actual incidence is not clear, there have been multiple studies showing that the incidence of anaphylaxis in the United States has increased in recent years [6–9], although the case fatality rate has decreased [8]. Similar findings are reported in other countries, with UK reporting increasing rates of anaphylaxis [10–12], but no increase in the incidence of fatal anaphylaxis [10]. In Australia the incidence of anaphylaxis [13–15] and fatal anaphylaxis has increased as well [16]. One study on the incidence of anaphylaxis with circulatory symptoms found a rate of approximately 8–9 cases per 100,000 persons per year [17]. Severe anaphylaxis, including respiratory or circulatory symptoms, occurs more frequently at a rate of about 1–3 per 10,000 people [18].

Factors that may affect the incidence of anaphylaxis include geography, seasonal

Anaphylaxis is caused by massive release of biochemical mediators from mast cell and basophils. Mast cells activation occurs mainly via antigen crosslinking of IgE bound to FcεRI receptors on cell membranes. However, other membrane receptors can activate mast cells as well or potentiate IgE activation [21]. The multiple activation pathways allow for immunologic (e.g. IgE mediated) and/or nonimmunologic activation (e.g. drug directly interacting with receptors) (**Figure 1**: mechanisms of mast cell degranulation). Some antigens may mediate effects via several mechanisms simultaneously (e.g. vespid venom, NSAIDs, opiates). In non-IgE mediated anaphylaxis, symptoms can occur on first exposure to an antigen as prior

Reproduced from Spoerl et al. [22] in agreement with publishing under terms of

In IgE mediated anaphylaxis, an immunogen cross links membrane bound IgE in previously sensitized mast cell. Immunogens are typically large foreign proteins

variations, age, and gender [19]. Demographic factors associated with higher

incidence include living in northern areas of US [7, 20].

exposure and sensitization is not required.

**3.1 Triggers and cell activation**

the Creative Commons Attribution (CC BY) license.

*1.1.2 Anaphylaxis*

*1.1.3 Anaphylactic shock*

**2. Epidemiology**

**3. Pathophysiology**

perfusion causing end organ damage.

**80**

*Mechanisms of mast cell degranulation. Abbreviations: RCM, radiocontrast media; TLR. Toll-like receptor; SCF, stem cell factor; FcεRI, high affinity IgE receptor; FcγR, IgG receptor; TCR, T-cell receptor; NMBA, neuromuscular blocking agent; PAF, platelet activating factor; MHC, major histocompatibility complex.*

with multiple epitope binding sites (e.g. proteins in insect venom and certain foods) [23]. Antigens that are too small to cross link IgE (e.g. penicillin) must first bind to larger carrier molecules in order to elicit an immune response. Common triggers of IgE-mediated anaphylaxis include various food, venom and medications are summarized in **Table 1**: IgE-dependent triggers and discussed in more detail below.

#### *3.1.1 Food*

The most common foods causing anaphylaxis varies by region, in North America the most common food allergies includes milk, egg, peanuts, tree nuts, fish, shellfish, wheat, soy, and sesame [24]. Allergenic proteins have been identified for these common causes as well as in rice, barley, buckwheat, mustard, celery, potato, carrots, and apples [25].

Most cases of anaphylaxis due to food occurs in children or those with known food allergies, and fatal cases are rare [7, 8, 10]. When fatal, the cause of death is more often due to respiratory arrest, although shock can occur as well. Arrest occurs later compared to medication or venom, typically occurring 25–35 min after exposure [26].

#### *3.1.2 Venom*

Stinging insects belonging to the order Hymenoptera produce venoms that can cause anaphylaxis. The important insects from this order include bees, vespids (wasps, yellow jackets, hornets) and stinging ants [27]. Vespid venom additionally activates complement in an IgE independent mechanism, which may potentiate anaphylaxis [28]. In addition to hymenoptera venom, bites from rattlesnakes [29],



#### **Table 1.**

*IgE-dependent triggers [9, 24, 27, 29–32].*

hamsters [30], and ticks [31] have been implicated as causes of anaphylaxis. Fatal cases due stings are more often due to shock than respiratory distress, arrest typically occurs 10–15 min after exposure [26].

#### *3.1.3 Medications*

The most common medications causing anaphylaxis are beta-lactam antibiotics, NSAIDs, neuromuscular blocking agents, and chemotherapy [9, 32] . However, nearly any medication has the potential to cause anaphylaxis, some drugs that have been implicated includes intravenous iron [33], gelatin found in a vaccines [34], dextran [35], and human serum albumin [36]. In addition to IgE mediated mechanisms, other mechanisms of inducing anaphylaxis have been identified for multiple drugs [37]. This includes complement or contact activation (e.g. radiocontrast media, pegylated compounds, liposomal drugs [38], and heparin contaminated with oversulfated chondroitin sulfate (OSCS) [39]) and direct mast cell activation (e.g. opiates and neuromuscular blockers [37]). There have been multiple reports of anaphylaxis occurring to biologic agents, where the patient had IgG but no detectable IgE antibody to the therapy [40]. In medication induced anaphylaxis, shock is more common in severe cases than respiratory distress [26, 41]. Arrest occurs can occur rapidly after exposure, most cases in less than 5 min [26].

#### **3.2 Biochemical mediators and clinical pharmacology**

Once activated, mast cells and basophils release a cascade of mediators which cause physiologic changes, activate other immunology pathways, and attract other immune cells. Preformed mediators are released immediately upon activation including histamine, tryptase, heparin, and chymase. Over several minutes additional mediators are generated including platelet activating factor, leukotrienes, and prostaglandins (**Table 2**). Various cytokines and chemokines are generated over several hours further propagate the inflammatory response [37, 42].

**83**

*Anaphylactic Shock*

Immediate release

Rapid generation

*Physiologic effects of mediators [42, 49].*

(min)

**Table 2.**

*DOI: http://dx.doi.org/10.5772/intechopen.88284*

receptor causes coronary vasoconstriction [45].

tion of other mediators [48, 49].

**4. Signs and Symptoms**

shock is still possible [26, 56].

with a range of 0.2–72 h [58].

**4.1 Cardiovascular changes**

Histamine has long been considered the principal mediator of anaphylaxis, and concentrations of histamine correlate with symptom severity [42]. Histamine acts on receptors to cause vasodilation and increased permeability [43, 44], bronchoconstriction, and increase mucus secretion. In the heart H2 receptors have positive chronotropic and ionotropic effects and causes coronary vasodilation, while the H1

Histamine Vasodilation, edema, bronchoconstriction, mucus secretion, change myocardial contractility

PAF Vasodilation, edema, bronchoconstriction, platelet activation, decrease myocardial contractility

Tryptase Vasodilation, edema, bronchoconstriction Chymase Vasodilation, edema, mucus secretion

LTs C4, D4 Potent vasoactive and spasmogenic agents Prostaglandin D2 Bronchospasm and increase mucus secretion

TNFa Bronchoconstriction

Heparin Initiates formation of bradykinin causing edema

Platelet activating factor (PAF) has been increasingly recognized as important in the pathophysiology of anaphylaxis. In PAF receptor knockout mice, symptoms of anaphylaxis are reduced [46]. In humans PAF levels in the serum directly correlates with the severity of anaphylaxis symptoms [47]. In addition to activating platelets, PAF causes vasodilation, increased vascular permeability, decreased myocardial contractility, bronchoconstriction, and initiates allergic response through stimula-

Anaphylaxis causes a generalized systemic reaction affecting multiple organ systems, symptoms involving the skin occur in 80–90% of cases, respiratory tract in 70%, GI in 45%, CV in 45%, and CNS involvement in 15% [50, 51]. The cardiovascular and respiratory systems are the principal shock organs in fatal anaphylaxis. Death occurs in most often due to shock or acute respiratory distress, but DIC and epinephrine overdose have also been cited as cause of death [26, 52–55]. Most fatal cases of anaphylaxis due to medication or venoms are a result of shock, in food related anaphylaxis respiratory involvement is the main cause of death although

Anaphylaxis develops rapidly with symptoms developing in minutes. Biphasic reactions, where symptoms resolve and then reappear later occurs around 20% of the time [57]. A systematic review of biphasic reactions found the medium time between resolution of initial symptoms and onset of delayed symptoms to be 11 h,

Cardiovascular manifestations of anaphylaxis develop due to direct and indirect effects of mediators on the vasculature and heart. Increased vascular permeability causes rapid fluid extravasation, with up to 35% of plasma volume shift occurring


#### **Table 2.**

*Clinical Management of Shock - The Science and Art of Physiological Restoration*

Bites/venoms Hymenoptera venom (bee, vespids\*

Eggs Peanuts Tree nuts Fish Shellfish Soy Wheat Sesame

Tick Rattlesnake Hamster

NSAIDs\* Chemotherapy Neuromuscular blocker\* Radiocontrast\* Opioids\*

, ants)

Foods Milk

Medications Antibiotics

*\*Non-IgE mediated mechanisms identified as alternative or additional mechanism.*

hamsters [30], and ticks [31] have been implicated as causes of anaphylaxis. Fatal cases due stings are more often due to shock than respiratory distress, arrest typi-

The most common medications causing anaphylaxis are beta-lactam antibiotics, NSAIDs, neuromuscular blocking agents, and chemotherapy [9, 32] . However, nearly any medication has the potential to cause anaphylaxis, some drugs that have been implicated includes intravenous iron [33], gelatin found in a vaccines [34], dextran [35], and human serum albumin [36]. In addition to IgE mediated mechanisms, other mechanisms of inducing anaphylaxis have been identified for multiple drugs [37]. This includes complement or contact activation (e.g. radiocontrast media, pegylated compounds, liposomal drugs [38], and heparin contaminated with oversulfated chondroitin sulfate (OSCS) [39]) and direct mast cell activation (e.g. opiates and neuromuscular blockers [37]). There have been multiple reports of anaphylaxis occurring to biologic agents, where the patient had IgG but no detectable IgE antibody to the therapy [40]. In medication induced anaphylaxis, shock is more common in severe cases than respiratory distress [26, 41]. Arrest occurs can occur rapidly after exposure, most cases in less

Once activated, mast cells and basophils release a cascade of mediators which cause physiologic changes, activate other immunology pathways, and attract other immune cells. Preformed mediators are released immediately upon activation including histamine, tryptase, heparin, and chymase. Over several minutes additional mediators are generated including platelet activating factor, leukotrienes, and prostaglandins (**Table 2**). Various cytokines and chemokines are generated over

cally occurs 10–15 min after exposure [26].

*IgE-dependent triggers [9, 24, 27, 29–32].*

**3.2 Biochemical mediators and clinical pharmacology**

several hours further propagate the inflammatory response [37, 42].

*3.1.3 Medications*

**Table 1.**

than 5 min [26].

**82**

*Physiologic effects of mediators [42, 49].*

Histamine has long been considered the principal mediator of anaphylaxis, and concentrations of histamine correlate with symptom severity [42]. Histamine acts on receptors to cause vasodilation and increased permeability [43, 44], bronchoconstriction, and increase mucus secretion. In the heart H2 receptors have positive chronotropic and ionotropic effects and causes coronary vasodilation, while the H1 receptor causes coronary vasoconstriction [45].

Platelet activating factor (PAF) has been increasingly recognized as important in the pathophysiology of anaphylaxis. In PAF receptor knockout mice, symptoms of anaphylaxis are reduced [46]. In humans PAF levels in the serum directly correlates with the severity of anaphylaxis symptoms [47]. In addition to activating platelets, PAF causes vasodilation, increased vascular permeability, decreased myocardial contractility, bronchoconstriction, and initiates allergic response through stimulation of other mediators [48, 49].
