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Anaphylaxis
Introduction
The Canadian Pediatric Surveillance Program defines anaphylaxis as severe systemic allergic reaction to any stimulus, having sudden onset and generally lasting less than 24 hours, involving one or more body systems and producing one or more symptoms such as hives, flushing, itching, angioedema, stridor, wheezing, shortness of breath, vomiting, diarrhea, or shock." Anaphylaxis involves multiple organ systems and is usually caused by specific antigens in sensitized individuals. Most anaphylactic reactions follow a uni-phasic reaction course. However, approximately 20% follow a biphasic course after an asymptomatic period of 1-8 hours. Protracted anaphylaxis may continue longer than 24 hours. Since anaphylaxis is a generalized reaction, anaphylaxis presents a wide variety of clinical signs and symptoms (Ellis et al., 2003). Anaphylaxis involves one or both of the following features: hypotension (which can present as fainting, collapse, or loss of consciousness) and respiratory difficulty (which may be due to laryngeal edema or asthma) (Ewan, 1998). Either respiratory obstruction or cardiovascular collapse, or both, are the cause of death. The more quickly anaphylactic symptoms appear, the more severe the reaction. In addition, patients often feel an impending sense of death" (Ellis et al., 2003). Anaphylaxis occurs when a person is reexposed to a specific antigen that cross-links antigenspecific IgE molecules, which are bound to mast cells and basophils. This leads to activation and degranulation of mast cells and basophils. Preformed mediators, such as histamine and tryptase, within the mast cell and basophil are released in degranulation. The metabolism of arachidonic acid in the cell membrane produces other mediators, such as prostaglandins and leukotrienes. These mediators act on receptors to induce mucus production, pruritus, vascular permeability, smooth-muscle constriction, and other symptoms of anaphylaxis (Rusznak, 2002). Rapid release of large quantities of mediators systemically will cause capillary leakage and mucosal edema, resulting in shock and asphyxia (Ewan, 1998). Immunological Mechanism of Anaphylaxis: (1) Antigen-presenting cell internalizes antigen. (2) The APC processes the internalized antigen. (3) The APC presents the processed peptide to CD4+ T lymphocytes via MHC II. (4) After the peptide is presented, the T cell differentiates into TH2 lymphocytes and produces IL-4, IL-5, IL-9, and IL-13. (5) IL-4 and IL-13 cause B cell immunoglobulin isotype switching to IgE. (6) The circulating IgE binds to the IgE receptors on mast cells. (7) Antigen similar to the original antigen cross-links the mast cell surface-bound IgE, resulting in cellular degranulation. Degranulation releases histamine, tryptase, and other mediators that produce the symptoms of anaphylaxis (Anaesthesia UK, 2005).

Figure 1: Overview of Immunological Mechanism of Anaphylaxis. This figure illustrates each step of the immunological mechanism for anaphylaxis. Figure taken from Anaesthesia UK( 2004), permission pending.

Mast Cell Activation

Figure 2: Activation of Mast Cell. This figure illustrates how activation of a mast cell leads to degranulation. Figure taken from Ewan(1998), permission pending.

It is important to note that anaphylactoid reactions involve activation of mast cells and release of the same mediators that cause the same effects as anaphylactic reactions, but the mechanism of mediator release in an anaphylactoid reaction is not IgE mediated. The inhibition of cyclooxygenase activity of Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) causes anaphylactoid reactions. Anaphylactoid reactions are also induced by radiocontrast agents, which cause direct mediator release from basophils and mast cells (Rusznak, 2002).

Etiology
The most common cause of anaphylaxis is food, which is followed by insect venom. Allergy to latex rubber is becoming a rapidly increasing problem because the use of latex rubber gloves in the medical field and also an increase in atopy. Exercise, vaccines, and semen account for rare causes of anaphylaxis. In addition, allergen immunotherapy(desensitization) may cause anaphylaxis (Ewan, 1998). See the following table outlining common causes of anaphylaxis.
Table 1 : Common Causes of Anaphylaxis. This table illustrates the common causes of anaphylaxis. Figure taken from Ewan(1998), permission pending.

Common causes of anaphylaxis

Foods Bee and wasp stings Drugs Latex rubber

Foods commonly causing anaphylaxis

Peanuts Tree nuts (eg, brazil nut, almond, hazelnut) Fish Shellfish Egg Milk Sesame Pulses (other than peanuts)

Drugs causing anaphylaxis or anaphylactoid reactions

Antibiotics (especially penicillin) Intravenous anesthetic drugs Aspirin Non-steroidal anti-inflammatory drugs Intravenous contrast media Opioid analgesics

Symptoms
The symptoms of anaphylaxis depend on the affected organ systems and severity of anaphylactic reaction. Monitoring patient's respiratory and cardiovascular status is critical because cardiovascular collapse or respiratory arrest could occur in severe cases. Vital signs may be

normal or significantly disordered with tachypnea, tachycardia, and/or hypotension. Shock may occur without prominent skin manifestations or history of exposure. Anaphylactic patients can become restless because urticaria may cause itchiness. The release of catecholamine may cause anxiety, tremor, and a sensation of cold (Krause, 2005). The following outline explains the symptoms that may occur if a particular organ system is affected by an anaphylactic reaction.

Clinical Signs and Symptoms of Anaphylaxis According to Different Organ Systems

Cutaneous o Flushing, pruritus, urticaria, angioedema, morbilliform rash, and pilor erecti o Local reaction Lesions occur near the site of a cutaneous exposure Involved area is erythematous, edematous, and pruritic If local skin reaction (as opposed to generalized urticaria) is present, systemic manifestations (e.g. respiratory distress) are less likely Even if severe reaction, local reactions are not predictive of systemic anaphylaxis on re-exposure o Lesions typical of angioedema can also Involve mucosal surfaces and deeper skin layers Appear on the lips, palms, soles, and genitalia Oral o Pruritus of lips, tongue, and palate and edema of lips and tongue; metallic taste in mouth Respiratory (major shock organ): o Laryngeal: pruritus and "tightness" in the throat, dysphagia, dysphonia and hoarseness, dry "staccato" cough, and itching in the external auditory canals; lung: shortness of breath, dyspnea, chest tightness, "deep" cough, and wheezing; nose: pruritus, congestion, rhinorrhea, and sneezing o Upper airway compromise may occur if tongue or oropharynx is involved o When the upper airway is involved, stridor may occur o Complete airway obstruction is the most common cause of death o Wheezing is common if bronchospasm or mucosal edema compromises lower airway o Marked edema of the tongue and lips may obstruct the airway in angioedema Cardiovascular o Faintness, syncope, chest pain, dysrhythmia, hypotension o Compensatory tachycardia often occurs due to loss of vascular tone in severe cases o Capillary leakage may cause intravascular volume depletion and hypotension Within 10 minutes of an anaphylactic reaction, as much as 50% of the intravascular fluid can leak into the extravascular space due to increased vascular permeability

Gastrointestinal o Nausea, abdominal pain (colic), vomiting (stringy mucus), diarrhea (Sampson, 2003, Krause, 2005, and Janeway, 2005)

The Effect of Mast Cell Activation on Different Tissues

Figure 3: The Effect of Mast Cell Activation on Different Tissues. This figure illustrates how the degranulation of mast cells affects various tissues in the body. Figure taken from Janeway(2005).

The Effect of Various Molecules Released by Mast Cells During Activation

Figure 4: The Effect of Various Molecules Released by Mast Cells During Activation. This figure shows the effect of various molecules released by mast cells on activation. Figure taken from Janeway(2005).

Table 2 : Physiological Effects of Mast Cell Mediators. This table illustrates the the physiological effects, symptoms, and dangers of mast cell mediators released in an anaphylactic reaction. Figure taken from Ewan(1998), permission pending.

Physiological effect Capillary leakage

Clinical expression Danger Urticaria Angio-edema Laryngeal edema Asphyxia

Hypotension Mucosal edema Laryngeal edema Rhinitis Asthma Smooth muscle contraction Asthma Abdominal pain

Shock Asphyxia Respiratory arrest Respiratory arrest

Treatments It is vital to be prepared and respond promptly with appropriate and aggressive treatment when treating anaphylaxis(Lieberman, 2005). The most important drug in treating anaphylaxis is epinephrine, which must be administered immediately. Epinephrine reverses the effects of anaphylaxis because it makes the heart pump faster, relaxes smooth muscle, widens air passages in the lung, contracts blood vessels,stops itching and hives, and relieves gastrointestinal cramping. After administering epinephrine, aminophylline, cortisone drugs, or antihistamines can be given to prevent acute symptoms from returning. Oxygen, intravenous fluids, and cardiac monitoring will help stabilize the heart, lungs, and blood pressure. Vasopressors and endotracheal intubation are other methods of treatment for anaphylaxis. Patients with anaphylaxis should be monitored overnight for at least six hours because there is a small chance of having a second anaphylactic reaction (Stern, 1997).

NOTE: If this picture is too small or blurry on your web browser, check the original source for a larger and more clear image. Figure 5: Mechanism for Relaxation of Smooth Muscles. This figure illustrates the mechanism of how epinephrine relaxes smooth muscle. Figure taken from Bunting(2000), permission pending.

Mechanism for How Epinephrine Relaxes Smooth Muscles (See Figure 5)

Epinephrine helps control relaxation and contraction of smooth muscle cells. Contraction occurs through binding of calmodulin to Calcium ions. The Calcium-Calmodulin complex then activates the myosin light chain kinase (MLCK), which in turn phosphorylates the myosin light chains to cause contraction. When epinephrine binds to an epinephrine receptor it activates adenylyl cyclase, which produces cyclic AMP(cAMP) from ATP. Then cAMP activates a protein kinase, which phosphorylates Myosin Light Chain Kinase (MLCK). Phosphorylation inactivates MLCK so it has a lower affinity for the Calcium-Calmodulin complex. This stops the downstream signal for muscle contraction, and thus, relaxes the smooth muscle tissue. Epinephrine also decreases the release and membrane permeability of histamine to reduce the effects of histamine (Bunting, 2000). Mechanism for How Epinephrine Raises Blood Pressure In the mechanism of raising blood pressure, epinephrine binds a beta-adrenergic receptor, which changes shape and activates a G-Protein, which activates Adenylyl Cyclase to convert ATP to cAMP. cAMP activates cAMP-dependent protein kinase (PKA). In cardiac muscle, PKA phosphorylates calcium channels in the plasma membrane and myosin heads. Phosphorylated calcium channels remain open longer and allow more calcium into the myocyte, which uncovers more myosin-binding sites on actin. This results in more cross-bridges formed, which creates a stronger force in myocyte contraction and a high blood pressure (Davidson College Biology Department, 2006). Prevention In order to prevent anaphylaxis, a person should avoid substances that cause anaphylaxis and alert their doctor/ health care providers of allergies. A person may carry an anaphylaxis kit with an Epi-Pen and get allergy shots to decrease the risk of anaphylaxis and severity of reactions (Lieberman, 2005).

Works Cited
Anaesthesia UK. 2004. Management of Latex Allergy. Anaesthesia UK. Accessed 24 April 2006 <http://www.anaesthesiauk.com/article.aspx?articleid=100086%00> Bunting, Heather et al. 2000. Epinephrine. Performance Enhancing Natural Products and Athletes. Accessed 24 April 2006 < http://www.udel.edu/chem/C465/senior/fall00/Performance1/indexa.htm.htm> Davidson College Biology Department. Epinephrine. Bio 111 Study Guide for Spring 2006 at Davidson College. Accessed 24 April 2006 < http://www.bio.davidson.edu/courses/bio111/stdygd/Chapters/SG06Sp.pdf>

Ellis, Anne and James Day. "Diagnosis and Management of Anaphylaxis " Canadian Medical Association Journal 169(2003): 1-4. Ewan,Pamela. "ABC of Allergies:Anaphylaxis" British Medical Journal 316 (1998): 1442-1445. Janeway, C.A., Travers, P., Walport, M., Schlomchik, M. Immunobiology 6th Ed: The Immune System in Health and Disease. New York: Garland Publishing, 2005. Krause, Richard. 29 April 2005. Anaphylaxis. eMedicine. Accessed 24 April 2006 <www.emedicine.com/emerg/topic25.htm> Lieberman P et al. "The Diagnosis and Management of Anaphylaxis:An Updated Practice Parameter." The Journal of Allergy and Clinical Immunology 115 (2005)483-523. Rusznak, Csaba. "Anaphylaxis and Anaphylactoid Reactions: A Guide to Prevention, Recognition, and Emergent Treatment." Postgraduate Medicine 111 (2002): 1-4. Sampson, Hugh. "Anaphylaxis and Emergency Treatment." Pediatrics 111 (2003): 1601-1608. Stern, David. 6 November 1997. Anaphylaxis:Life-Threatening Allergy. Asthma and Allergy Information and Research. Accessed 24 April 2006 < http://www.users.globalnet.co.uk/~aair/index.htm