- Email: [email protected]
Allergic Reactions and Angioedema
Allergic Reactions and Angioedema Dominique Cosco,
MD,
Neil Winawer,
MD, SFHM*
KEYWORDS Allergy Allergic reactions Anaphylaxis Angioedema
HOSPITAL MEDICINE CLINICS CHECKLIST
1. Allergic reactions are immunoglobulin E (IgE) antibody mediated and cause an immediate hypersensitivity reaction. Anaphylaxis is a potentially fatal hypersensitivity reaction involving multiple organ systems that occurs seconds to minutes following exposure to the inciting antigen. 2. In adults, insect stings and medications are the most common triggers for anaphylaxis, whereas foods remain the most common triggers in children. 3. Skin features are the predominant examination finding in allergic reactions and may include flushing, urticaria, and pruritus. 4. Clinical findings for anaphylaxis include skin features as well as respiratory, gastrointestinal, and cardiovascular signs and symptoms. 5. Although diagnostic criteria exist to diagnose anaphylaxis, clinically it is important to recognize and treat anaphylaxis immediately. 6. Laboratory data are rarely needed to diagnosis allergic reactions or anaphylaxis. 7. Epinephrine is the keystone for management of anaphylaxis. For mast cell– mediated reactions, antihistamines and corticosteroids can be used. 8. In-hospital allergic reactions and anaphylaxis should be treated the same way, although these reactions should prompt clinicians to investigate specific triggers. 9. Patients with airway compromise or additional organ system involvement suggestive of anaphylaxis should be admitted for a minimum of 24 hours for close monitoring.
Disclosures: The authors have no conflicts of interest or funding sources to disclose. Department of Medicine, Grady Memorial Hospital, Emory University School of Medicine, 49 Jessie Hill Jr Drive, Atlanta, GA 30303, USA * Corresponding author. E-mail address: [email protected] Hosp Med Clin - (2015) -–http://dx.doi.org/10.1016/j.ehmc.2015.06.004 2211-5943/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
2
Cosco & Winawer
DEFINITIONS
How are allergic reactions defined? An allergic reaction is an overreaction by the immune system, producing immunoglobulin E (IgE) antibody to an otherwise harmless antigen or allergen. The antibody binds to high-affinity IgE receptors on the surface of mast cells and basophils, resulting in sensitization to that antigen. Repeated exposure to the allergen results in cross-linking of mast cell and basophil-bound IgE antibodies, triggering the release of inflammatory mediators (eg, histamine, tryptase, leukotrienes) that cause smooth muscle contraction, vasodilatation, increased vascular permeability, and edema. What is anaphylaxis? Anaphylaxis is a potentially fatal hypersensitivity reaction involving multiple organ systems that occurs seconds to minutes following exposure to the inciting antigen. What is an anaphylactoid reaction? Anaphylactoid reactions present with features that are clinically indistinguishable from anaphylaxis; however, the underlying mechanisms are nonimmunologic (not IgE mediated). Anaphylactoid reactions can be caused by opiates, angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs), and radiocontrast dye. Given their similar presentations and treatments, severe IgE-mediated immediate hypersensitivity reactions and anaphylactoid reactions are often grouped together under the general term anaphylaxis. EPIDEMIOLOGY
What is the prevalence of anaphylaxis? Estimates of anaphylaxis prevalence vary widely depending on the population being studied as well as the various trial designs used. Evidence suggests that the prevalence of anaphylaxis is increasing.1 In the United States, the most recent estimation of lifetime prevalence of anaphylaxis is 1.6%. However, this number is thought to be an underestimation because many cases of anaphylaxis are undiagnosed or mistaken for other disease processes.2 What are the most common triggers of anaphylaxis? In adults, insect stings and medications are the most common triggers, whereas foods remain the most common triggers in children. Other triggers for anaphylaxis in adults include natural latex items, biologic medications, and occupational exposures. Anaphylaxis can also be caused by idiopathic agents, IgE-independent mechanisms, and direct activation of mast cells. Box 1 lists common triggers of anaphylaxis. Are there comorbidities that increase the risk of anaphylaxis? Asthma can increase the risk for anaphylaxis. Concurrent cardiovascular disease and chronic pulmonary conditions can increase the risk of death from anaphylaxis.
Allergic Reactions and Angioedema
Box 1 Common triggers of anaphylaxis Allergen (IgE mediated) Medications Insect stings and bites Food triggers Natural latex items Biologic medications IgE independent Exercise induced Medications (opiates, ACE inhibitors, NSAIDs) Radiocontrast dye Data from Lieberman P, Nicklas RA, Oppenheimer J, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010;126(3):477–80.
HISTORY AND EXAMINATION
What are the clinical features in patients presenting with allergic reactions and angioedema? The clinical features of allergic reactions vary widely. Given the large number of mast cells in the dermis and deeper structures, skin features are the predominant examination finding and may include flushing, urticaria, and pruritus. Factors such as the route of entry of the allergen as well as the amount and duration of exposure to the allergen can affect the clinical presentation. Angioedema is characterized by nonpruritic, nonpitting edema of the subcutaneous and submucosal layers, most commonly in the face, extremities, genital areas, or abdominal viscera. What are the clinical features of patients presenting with anaphylaxis? In addition to the cutaneous findings associated with allergic reactions, patients may also show respiratory, gastrointestinal, and cardiovascular manifestations. Box 2 lists the clinical features associated with allergic reactions and anaphylaxis. DIAGNOSIS
What are the diagnostic criteria for anaphylaxis? Consensus diagnostic criteria for anaphylaxis have been published by an expert panel with the goal of helping clinicians recognize the spectrum of signs and symptoms.2,3 Anaphylaxis is considered highly likely when any one of the following criteria is met: 1. Acute onset of illness involving skin (flushing, pruritus, urticaria), mucosa (angioedema), or both; and one of the following: Respiratory compromise Low systolic blood pressure or signs of end-organ damage
3
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Cosco & Winawer
Box 2 Clinical symptoms of allergic reactions and anaphylaxis Skin symptoms Flushing Pruritus Urticaria Angioedema Respiratory symptoms Hoarseness/change in voice Dyspnea Wheezing Cough Chest tightness Gastrointestinal symptoms Nausea Vomiting Diarrhea Colicky or crampy abdominal pain Cardiovascular symptoms Peripheral vasodilation Dizziness Reflex tachycardia Hypotension Syncope Data from Manning KD, Winawer NH, Murali MR. Allergy and anaphylaxis. In: McKean SC, Ross JJ, Dressler DD, et al, editors. Principles and practice of hospital medicine. McGraw-Hill; 2012. p. 1975–80.
2. Two or more of the following symptoms that occur rapidly after exposure to a likely antigen: Symptoms of the skin or mucosal tissue Respiratory compromise Low systolic blood pressure or signs of end-organ damage Persistent gastrointestinal symptoms 3. Low systolic blood pressure after exposure to a known allergen (systolic blood pressure <90 mm Hg or 30% decrease from patient’s known baseline) What is the differential diagnosis for anaphylaxis? The differential diagnosis for anaphylaxis includes multiple disease processes, including common disorders such as vasovagal reactions, bronchoconstriction or bronchospasm, syncope, panic attacks, and hypoglycemia. The cutaneous
Allergic Reactions and Angioedema
findings associated with 90% of anaphylaxis reactions can be helpful in diagnosis because they are absent in other conditions.4 Box 3 highlights disease processes that should be considered in the differential diagnosis for anaphylaxis. What laboratory tests are used to diagnose the cause of anaphylaxis? The diagnosis of allergic reactions and anaphylaxis is based on the clinical presentation and the diagnostic criteria, as outlined earlier. Laboratory evaluation is rarely needed to make the diagnosis. However, laboratory evaluation may be of use when clinical uncertainty exists and a mast cell–mediated anaphylactic/anaphylactoid reaction is suspected. Serum tryptase levels, both total and beta tryptase, can be useful in aiding in the diagnosis of anaphylactoid reactions, such as systemic mastocytosis, in which the total level are increased with a normal beta level. In contrast, beta tryptase levels are increased in anaphylaxis.5 However, in both cases, serum must be obtained immediately on presentation to the hospital because levels only remain increased for hours following initial symptoms. In cases in which hereditary angioedema is considered, a normal complement C4 level is an effective screening test in ruling out disease, because it is typically consumed in the setting of C1 esterase deficiency. A 24-hour urine level for 5-hydroxyindoleactetic acid can aid in the diagnosis of carcinoid syndrome.5
Box 3 Differential diagnosis for anaphylaxis Common disease processes Vasovagal reactions Bronchoconstriction/bronchospasm Syncope Panic/anxiety attack Hypoglycemia Bradykinin-mediated reactions ACE-inhibitor angioedema Hereditary angioedema Flushing reactions Carcinoid syndrome Overproduction of histamine Systemic mastocytosis (overabundance of mast cells in skin, liver, spleen, gastrointestinal tract, bone marrow) Other Vocal cord dysfunction Data from Manning KD, Winawer NH, Murali MR. Allergy and anaphylaxis. In: McKean SC, Ross JJ, Dressler DD, et al, editors. Principles and practice of hospital medicine. McGraw-Hill; 2012. p. 1975–80.
5
6
Cosco & Winawer
MANAGEMENT
What are the initial management strategies for severe allergic reactions or anaphylaxis? The most important management steps are immediate recognition and prompt treatment. Patients with mast cell–mediated reactions are managed with histamine H1-receptor blockers and corticosteroids. Bronchoconstriction is treated with beta agonists. If the reaction is systemic (anaphylaxis), epinephrine is used. These agents have limited effectiveness in the treatment of bradykinin-mediated reactions (ACEinhibitor angioedema and hereditary angioedema) because they are not mast cell mediated. What patients with allergic reactions require admission? The decision to admit a patient with an allergic reaction depends on the severity and symptoms of the reaction as well as the patient’s initial response to treatment. Patients with only cutaneous symptoms can be monitored in the emergency department and discharged home if they respond to therapy. Patients who present with respiratory symptoms or other organ involvement, suggestive of anaphylaxis, should be treated as a medical emergency with focused attention on airway patency, hemodynamics, and cardiopulmonary status. Patients who respond to therapy should still be monitored in the inpatient setting for 24 hours because biphasic reactions (recurrence of symptoms that typically occur hours after resolution of the initial anaphylactic event) have been documented in as many as 20% of patients.6 Any patient with laryngeal edema or anticipated airway compromise should be admitted to an intensive care unit for airway monitoring. In addition, if a patient does not respond to initial therapies, intensive care admission is warranted. What is the management for allergic reactions that occur during hospitalization? Management of allergic reactions in the hospital setting is the same as those occurring in the outpatient setting. However, allergic reactions that develop in the hospital should alert the clinician to consider specific triggers. Box 4 highlights triggers that should be considered for allergic reactions occurring in the hospital setting. Given that parental administration of an allergen induces more severe responses than oral ingestion, allergic reactions in the hospital may occur more frequently or have more severe manifestations. What are the pharmacologic agents used to treat allergic reactions and anaphylaxis? Any patient with a severe allergic reaction or anaphylaxis should receive epinephrine as an intramuscular injection to the outer thigh. The intramuscular epinephrine dose is 0.3 to 0.5 mg (1 mg per mL). If a patient is experiencing respiratory distress or hypotension concerning for shock, epinephrine should be administered intravenously at a slow rate of 0.1 mg over 5 to 10 minutes. If patients fail to respond to the intravenous dose, a continuous intravenous infusion may be started at a rate of 1 to 4 mg/min in a closely monitored setting.7 Patients with severe respiratory distress or airway edema require immediate intubation to prevent airway compromise.
Allergic Reactions and Angioedema
Box 4 Allergic reaction triggers in the hospital setting Antibiotics b-Lactam antibiotics (specifically, penicillin or penicillin analogues) Cephalosporins (if patient has true anaphylaxis to penicillins because there is a 50% cross reactivity) Latex products Anaphylactoid reactions Radiocontrast dye Opiates NSAIDs Aspirin Chemotherapeutic drugs Carboplatinum Cisplatinum Monoclonal biologic medications Cetuximab Rituximab Data from Manning KD, Winawer NH, Murali MR. Allergy and anaphylaxis. In: McKean SC, Ross JJ, Dressler DD, et al, editors. Principles and practice of hospital medicine. McGraw-Hill; 2012. p. 1975–80.
Box 5 lists other pharmacologic agents that can be used to treat severe allergic reactions and anaphylaxis. However, none of these agents should be substituted for epinephrine as the first-line agent for treatment. It is the only medication shown to be lifesaving in anaphylaxis. Patients with a history of hypersensitivity reactions to radiocontrast often require further radiographic testing. How are these patients treated? Any patient with severe, life-threatening reactions to radiocontrast should not be administered the same agent. Although there are many options for predosing patients before radiographic procedures, the most common involves administering prednisone (50 mg in adults) 13 hours, 7 hours, and 1 hour before the procedure with diphenhydramine (50 mg in adults) intravenous/oral 1 hour before the procedure along with nonionic low-osmolar contrast material. Should patients with a history of ACE-inhibitor angioedema receive angiotensin receptor blockers (ARBs)? Patients with a history of ACE-inhibitor angioedema generally tolerate ARBs; however, they should be used with caution given case reports of angioedema on these agents. Treatment in these instances should be individualized. If the patient has a strong indication for treatment with an ARB (eg, diabetic nephropathy) and the episode of angioedema was nonlife threatening, then the ARB should be prescribed while educating the patient on the small potential for cross reactivity.
7
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Cosco & Winawer
Box 5 Pharmacologic agents used in the treatment of severe allergic reactions and anaphylaxis Epinephrine (see details in text) Should always be the first agent administered for its ability to help relieve airway obstruction, and reverse hypotension and shock Antihistamines H1-receptor blockers to help relieve itching and urticaria May use H2 receptor blockers as an adjunct Corticosteroids Can help to reduce inflammation and vascular permeability Used as an adjunct or when antihistamines are unable to decrease edema Bronchodilators Albuterol nebulizer Glucagon Should be used in patients taking beta blockers who are resistant to epinephrine treatment and develop refractory hypotension and bradycardia Recommended dose is 1 to 5 mg administered intravenously over 5 to 10 minutes Intravenous fluid Recommended for hypotensive patients Vasopressor therapy Epinephrine or phenylephrine intravenous drip for patients who do not respond to epinephrine injection and IVF resuscitation Data from Simons FE. Anaphylaxis. J Allergy Clin Immunol 2010;125(2 Suppl 2):S161–81.
PROGNOSIS
What is the prognosis for patients who present with anaphylaxis? Patients who have experienced anaphylaxis are at risk for recurrent episodes. However, the long-term prognosis for patients with anaphylaxis is generally favorable provided patients are educated on the nature of their disease process. Particular emphasis should be placed on understanding and avoiding potential triggers as well as initiating prompt treatment with epinephrine at the first sign of an attack. Patients should be informed about wearing medical alert bracelets and provided instructions on how to properly use an epinephrine autoinjector. If the offending agent is unknown, patients should be instructed to follow with an allergist for skin testing. The acronym SAFE is a simple and often used mnemonic to prompt physicians on the 4 basic action steps for the care of patients with anaphylaxis: (1) seek support, (2) allergen identification and avoidance, (3) follow-up for specialty care, and (4) epinephrine for emergencies.8 PERFORMANCE IMPROVEMENT
Initiatives to improve anaphylaxis care typically have focused on improving clinician recognition of anaphylaxis along with prompt epinephrine treatment. One study in a
Allergic Reactions and Angioedema
pediatric emergency department revealed that instituting an anaphylaxis protocol resulted in a significant increase in the use of epinephrine (27%–58%).9 Another initiative focused on education in schools by providing faculty with instructional videos along with free epinephrine autoinjectors. CLINICAL GUIDELINES
Muraro A, Roberts G, Worm M, et al, EAACI Food Allergy and Anaphylaxis Guidelines Group. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy 2014;69(8):1026–45. Simons FE, Ardusso LR, Dimov V, et al. World Allergy Organization Anaphylaxis Guidelines: 2013 update of the evidence base. Intl Arch of Allergy Immunol 2013;162(3):193–204. REFERENCES
1. Ma L, Danoff TM, Borish L. Case fatality and population mortality associated with anaphylaxis in the United States. J Allergy Clin Immunol 2014;133(4):1075–83. 2. Wood RA, Camargo CA Jr, Lieberman P, et al. Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States. J Allergy Clin Immunol 2014;133(2):461–7. 3. Sampson HA, Mun˜oz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117(2):391–7. 4. Simons FE. Anaphylaxis. J Allergy Clin Immunol 2010;125(2 Suppl 2):S161–81. 5. Manning KD, Winawer NH, Murali MR. Allergy and anaphylaxis. In: McKean SC, Ross JJ, Dressler DD, et al, editors. Principles and practice of hospital medicine. McGraw-Hill; 2012. p. 1975–80. 6. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005; 95(3):217–26. 7. Anchor J, Settipane RA. Appropriate use of epinephrine in anaphylaxis. Am J Emerg Med 2004;22:488–90. 8. Lieberman P, Decker W, Camargo CA Jr, et al. SAFE: a multidisciplinary approach to anaphylaxis education in the emergency department. Ann Allergy Asthma Immunol 2007;98(6):519–23. 9. Arroabarren E, Lasa EM, Olaciregui I, et al. Improving anaphylaxis management in a pediatric emergency department. Pediatr Allergy Immunol 2011;22(7):708–14.
9
MD,
Neil Winawer,
MD, SFHM*
KEYWORDS Allergy Allergic reactions Anaphylaxis Angioedema
HOSPITAL MEDICINE CLINICS CHECKLIST
1. Allergic reactions are immunoglobulin E (IgE) antibody mediated and cause an immediate hypersensitivity reaction. Anaphylaxis is a potentially fatal hypersensitivity reaction involving multiple organ systems that occurs seconds to minutes following exposure to the inciting antigen. 2. In adults, insect stings and medications are the most common triggers for anaphylaxis, whereas foods remain the most common triggers in children. 3. Skin features are the predominant examination finding in allergic reactions and may include flushing, urticaria, and pruritus. 4. Clinical findings for anaphylaxis include skin features as well as respiratory, gastrointestinal, and cardiovascular signs and symptoms. 5. Although diagnostic criteria exist to diagnose anaphylaxis, clinically it is important to recognize and treat anaphylaxis immediately. 6. Laboratory data are rarely needed to diagnosis allergic reactions or anaphylaxis. 7. Epinephrine is the keystone for management of anaphylaxis. For mast cell– mediated reactions, antihistamines and corticosteroids can be used. 8. In-hospital allergic reactions and anaphylaxis should be treated the same way, although these reactions should prompt clinicians to investigate specific triggers. 9. Patients with airway compromise or additional organ system involvement suggestive of anaphylaxis should be admitted for a minimum of 24 hours for close monitoring.
Disclosures: The authors have no conflicts of interest or funding sources to disclose. Department of Medicine, Grady Memorial Hospital, Emory University School of Medicine, 49 Jessie Hill Jr Drive, Atlanta, GA 30303, USA * Corresponding author. E-mail address: [email protected] Hosp Med Clin - (2015) -–http://dx.doi.org/10.1016/j.ehmc.2015.06.004 2211-5943/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
2
Cosco & Winawer
DEFINITIONS
How are allergic reactions defined? An allergic reaction is an overreaction by the immune system, producing immunoglobulin E (IgE) antibody to an otherwise harmless antigen or allergen. The antibody binds to high-affinity IgE receptors on the surface of mast cells and basophils, resulting in sensitization to that antigen. Repeated exposure to the allergen results in cross-linking of mast cell and basophil-bound IgE antibodies, triggering the release of inflammatory mediators (eg, histamine, tryptase, leukotrienes) that cause smooth muscle contraction, vasodilatation, increased vascular permeability, and edema. What is anaphylaxis? Anaphylaxis is a potentially fatal hypersensitivity reaction involving multiple organ systems that occurs seconds to minutes following exposure to the inciting antigen. What is an anaphylactoid reaction? Anaphylactoid reactions present with features that are clinically indistinguishable from anaphylaxis; however, the underlying mechanisms are nonimmunologic (not IgE mediated). Anaphylactoid reactions can be caused by opiates, angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs), and radiocontrast dye. Given their similar presentations and treatments, severe IgE-mediated immediate hypersensitivity reactions and anaphylactoid reactions are often grouped together under the general term anaphylaxis. EPIDEMIOLOGY
What is the prevalence of anaphylaxis? Estimates of anaphylaxis prevalence vary widely depending on the population being studied as well as the various trial designs used. Evidence suggests that the prevalence of anaphylaxis is increasing.1 In the United States, the most recent estimation of lifetime prevalence of anaphylaxis is 1.6%. However, this number is thought to be an underestimation because many cases of anaphylaxis are undiagnosed or mistaken for other disease processes.2 What are the most common triggers of anaphylaxis? In adults, insect stings and medications are the most common triggers, whereas foods remain the most common triggers in children. Other triggers for anaphylaxis in adults include natural latex items, biologic medications, and occupational exposures. Anaphylaxis can also be caused by idiopathic agents, IgE-independent mechanisms, and direct activation of mast cells. Box 1 lists common triggers of anaphylaxis. Are there comorbidities that increase the risk of anaphylaxis? Asthma can increase the risk for anaphylaxis. Concurrent cardiovascular disease and chronic pulmonary conditions can increase the risk of death from anaphylaxis.
Allergic Reactions and Angioedema
Box 1 Common triggers of anaphylaxis Allergen (IgE mediated) Medications Insect stings and bites Food triggers Natural latex items Biologic medications IgE independent Exercise induced Medications (opiates, ACE inhibitors, NSAIDs) Radiocontrast dye Data from Lieberman P, Nicklas RA, Oppenheimer J, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010;126(3):477–80.
HISTORY AND EXAMINATION
What are the clinical features in patients presenting with allergic reactions and angioedema? The clinical features of allergic reactions vary widely. Given the large number of mast cells in the dermis and deeper structures, skin features are the predominant examination finding and may include flushing, urticaria, and pruritus. Factors such as the route of entry of the allergen as well as the amount and duration of exposure to the allergen can affect the clinical presentation. Angioedema is characterized by nonpruritic, nonpitting edema of the subcutaneous and submucosal layers, most commonly in the face, extremities, genital areas, or abdominal viscera. What are the clinical features of patients presenting with anaphylaxis? In addition to the cutaneous findings associated with allergic reactions, patients may also show respiratory, gastrointestinal, and cardiovascular manifestations. Box 2 lists the clinical features associated with allergic reactions and anaphylaxis. DIAGNOSIS
What are the diagnostic criteria for anaphylaxis? Consensus diagnostic criteria for anaphylaxis have been published by an expert panel with the goal of helping clinicians recognize the spectrum of signs and symptoms.2,3 Anaphylaxis is considered highly likely when any one of the following criteria is met: 1. Acute onset of illness involving skin (flushing, pruritus, urticaria), mucosa (angioedema), or both; and one of the following: Respiratory compromise Low systolic blood pressure or signs of end-organ damage
3
4
Cosco & Winawer
Box 2 Clinical symptoms of allergic reactions and anaphylaxis Skin symptoms Flushing Pruritus Urticaria Angioedema Respiratory symptoms Hoarseness/change in voice Dyspnea Wheezing Cough Chest tightness Gastrointestinal symptoms Nausea Vomiting Diarrhea Colicky or crampy abdominal pain Cardiovascular symptoms Peripheral vasodilation Dizziness Reflex tachycardia Hypotension Syncope Data from Manning KD, Winawer NH, Murali MR. Allergy and anaphylaxis. In: McKean SC, Ross JJ, Dressler DD, et al, editors. Principles and practice of hospital medicine. McGraw-Hill; 2012. p. 1975–80.
2. Two or more of the following symptoms that occur rapidly after exposure to a likely antigen: Symptoms of the skin or mucosal tissue Respiratory compromise Low systolic blood pressure or signs of end-organ damage Persistent gastrointestinal symptoms 3. Low systolic blood pressure after exposure to a known allergen (systolic blood pressure <90 mm Hg or 30% decrease from patient’s known baseline) What is the differential diagnosis for anaphylaxis? The differential diagnosis for anaphylaxis includes multiple disease processes, including common disorders such as vasovagal reactions, bronchoconstriction or bronchospasm, syncope, panic attacks, and hypoglycemia. The cutaneous
Allergic Reactions and Angioedema
findings associated with 90% of anaphylaxis reactions can be helpful in diagnosis because they are absent in other conditions.4 Box 3 highlights disease processes that should be considered in the differential diagnosis for anaphylaxis. What laboratory tests are used to diagnose the cause of anaphylaxis? The diagnosis of allergic reactions and anaphylaxis is based on the clinical presentation and the diagnostic criteria, as outlined earlier. Laboratory evaluation is rarely needed to make the diagnosis. However, laboratory evaluation may be of use when clinical uncertainty exists and a mast cell–mediated anaphylactic/anaphylactoid reaction is suspected. Serum tryptase levels, both total and beta tryptase, can be useful in aiding in the diagnosis of anaphylactoid reactions, such as systemic mastocytosis, in which the total level are increased with a normal beta level. In contrast, beta tryptase levels are increased in anaphylaxis.5 However, in both cases, serum must be obtained immediately on presentation to the hospital because levels only remain increased for hours following initial symptoms. In cases in which hereditary angioedema is considered, a normal complement C4 level is an effective screening test in ruling out disease, because it is typically consumed in the setting of C1 esterase deficiency. A 24-hour urine level for 5-hydroxyindoleactetic acid can aid in the diagnosis of carcinoid syndrome.5
Box 3 Differential diagnosis for anaphylaxis Common disease processes Vasovagal reactions Bronchoconstriction/bronchospasm Syncope Panic/anxiety attack Hypoglycemia Bradykinin-mediated reactions ACE-inhibitor angioedema Hereditary angioedema Flushing reactions Carcinoid syndrome Overproduction of histamine Systemic mastocytosis (overabundance of mast cells in skin, liver, spleen, gastrointestinal tract, bone marrow) Other Vocal cord dysfunction Data from Manning KD, Winawer NH, Murali MR. Allergy and anaphylaxis. In: McKean SC, Ross JJ, Dressler DD, et al, editors. Principles and practice of hospital medicine. McGraw-Hill; 2012. p. 1975–80.
5
6
Cosco & Winawer
MANAGEMENT
What are the initial management strategies for severe allergic reactions or anaphylaxis? The most important management steps are immediate recognition and prompt treatment. Patients with mast cell–mediated reactions are managed with histamine H1-receptor blockers and corticosteroids. Bronchoconstriction is treated with beta agonists. If the reaction is systemic (anaphylaxis), epinephrine is used. These agents have limited effectiveness in the treatment of bradykinin-mediated reactions (ACEinhibitor angioedema and hereditary angioedema) because they are not mast cell mediated. What patients with allergic reactions require admission? The decision to admit a patient with an allergic reaction depends on the severity and symptoms of the reaction as well as the patient’s initial response to treatment. Patients with only cutaneous symptoms can be monitored in the emergency department and discharged home if they respond to therapy. Patients who present with respiratory symptoms or other organ involvement, suggestive of anaphylaxis, should be treated as a medical emergency with focused attention on airway patency, hemodynamics, and cardiopulmonary status. Patients who respond to therapy should still be monitored in the inpatient setting for 24 hours because biphasic reactions (recurrence of symptoms that typically occur hours after resolution of the initial anaphylactic event) have been documented in as many as 20% of patients.6 Any patient with laryngeal edema or anticipated airway compromise should be admitted to an intensive care unit for airway monitoring. In addition, if a patient does not respond to initial therapies, intensive care admission is warranted. What is the management for allergic reactions that occur during hospitalization? Management of allergic reactions in the hospital setting is the same as those occurring in the outpatient setting. However, allergic reactions that develop in the hospital should alert the clinician to consider specific triggers. Box 4 highlights triggers that should be considered for allergic reactions occurring in the hospital setting. Given that parental administration of an allergen induces more severe responses than oral ingestion, allergic reactions in the hospital may occur more frequently or have more severe manifestations. What are the pharmacologic agents used to treat allergic reactions and anaphylaxis? Any patient with a severe allergic reaction or anaphylaxis should receive epinephrine as an intramuscular injection to the outer thigh. The intramuscular epinephrine dose is 0.3 to 0.5 mg (1 mg per mL). If a patient is experiencing respiratory distress or hypotension concerning for shock, epinephrine should be administered intravenously at a slow rate of 0.1 mg over 5 to 10 minutes. If patients fail to respond to the intravenous dose, a continuous intravenous infusion may be started at a rate of 1 to 4 mg/min in a closely monitored setting.7 Patients with severe respiratory distress or airway edema require immediate intubation to prevent airway compromise.
Allergic Reactions and Angioedema
Box 4 Allergic reaction triggers in the hospital setting Antibiotics b-Lactam antibiotics (specifically, penicillin or penicillin analogues) Cephalosporins (if patient has true anaphylaxis to penicillins because there is a 50% cross reactivity) Latex products Anaphylactoid reactions Radiocontrast dye Opiates NSAIDs Aspirin Chemotherapeutic drugs Carboplatinum Cisplatinum Monoclonal biologic medications Cetuximab Rituximab Data from Manning KD, Winawer NH, Murali MR. Allergy and anaphylaxis. In: McKean SC, Ross JJ, Dressler DD, et al, editors. Principles and practice of hospital medicine. McGraw-Hill; 2012. p. 1975–80.
Box 5 lists other pharmacologic agents that can be used to treat severe allergic reactions and anaphylaxis. However, none of these agents should be substituted for epinephrine as the first-line agent for treatment. It is the only medication shown to be lifesaving in anaphylaxis. Patients with a history of hypersensitivity reactions to radiocontrast often require further radiographic testing. How are these patients treated? Any patient with severe, life-threatening reactions to radiocontrast should not be administered the same agent. Although there are many options for predosing patients before radiographic procedures, the most common involves administering prednisone (50 mg in adults) 13 hours, 7 hours, and 1 hour before the procedure with diphenhydramine (50 mg in adults) intravenous/oral 1 hour before the procedure along with nonionic low-osmolar contrast material. Should patients with a history of ACE-inhibitor angioedema receive angiotensin receptor blockers (ARBs)? Patients with a history of ACE-inhibitor angioedema generally tolerate ARBs; however, they should be used with caution given case reports of angioedema on these agents. Treatment in these instances should be individualized. If the patient has a strong indication for treatment with an ARB (eg, diabetic nephropathy) and the episode of angioedema was nonlife threatening, then the ARB should be prescribed while educating the patient on the small potential for cross reactivity.
7
8
Cosco & Winawer
Box 5 Pharmacologic agents used in the treatment of severe allergic reactions and anaphylaxis Epinephrine (see details in text) Should always be the first agent administered for its ability to help relieve airway obstruction, and reverse hypotension and shock Antihistamines H1-receptor blockers to help relieve itching and urticaria May use H2 receptor blockers as an adjunct Corticosteroids Can help to reduce inflammation and vascular permeability Used as an adjunct or when antihistamines are unable to decrease edema Bronchodilators Albuterol nebulizer Glucagon Should be used in patients taking beta blockers who are resistant to epinephrine treatment and develop refractory hypotension and bradycardia Recommended dose is 1 to 5 mg administered intravenously over 5 to 10 minutes Intravenous fluid Recommended for hypotensive patients Vasopressor therapy Epinephrine or phenylephrine intravenous drip for patients who do not respond to epinephrine injection and IVF resuscitation Data from Simons FE. Anaphylaxis. J Allergy Clin Immunol 2010;125(2 Suppl 2):S161–81.
PROGNOSIS
What is the prognosis for patients who present with anaphylaxis? Patients who have experienced anaphylaxis are at risk for recurrent episodes. However, the long-term prognosis for patients with anaphylaxis is generally favorable provided patients are educated on the nature of their disease process. Particular emphasis should be placed on understanding and avoiding potential triggers as well as initiating prompt treatment with epinephrine at the first sign of an attack. Patients should be informed about wearing medical alert bracelets and provided instructions on how to properly use an epinephrine autoinjector. If the offending agent is unknown, patients should be instructed to follow with an allergist for skin testing. The acronym SAFE is a simple and often used mnemonic to prompt physicians on the 4 basic action steps for the care of patients with anaphylaxis: (1) seek support, (2) allergen identification and avoidance, (3) follow-up for specialty care, and (4) epinephrine for emergencies.8 PERFORMANCE IMPROVEMENT
Initiatives to improve anaphylaxis care typically have focused on improving clinician recognition of anaphylaxis along with prompt epinephrine treatment. One study in a
Allergic Reactions and Angioedema
pediatric emergency department revealed that instituting an anaphylaxis protocol resulted in a significant increase in the use of epinephrine (27%–58%).9 Another initiative focused on education in schools by providing faculty with instructional videos along with free epinephrine autoinjectors. CLINICAL GUIDELINES
Muraro A, Roberts G, Worm M, et al, EAACI Food Allergy and Anaphylaxis Guidelines Group. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy 2014;69(8):1026–45. Simons FE, Ardusso LR, Dimov V, et al. World Allergy Organization Anaphylaxis Guidelines: 2013 update of the evidence base. Intl Arch of Allergy Immunol 2013;162(3):193–204. REFERENCES
1. Ma L, Danoff TM, Borish L. Case fatality and population mortality associated with anaphylaxis in the United States. J Allergy Clin Immunol 2014;133(4):1075–83. 2. Wood RA, Camargo CA Jr, Lieberman P, et al. Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States. J Allergy Clin Immunol 2014;133(2):461–7. 3. Sampson HA, Mun˜oz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117(2):391–7. 4. Simons FE. Anaphylaxis. J Allergy Clin Immunol 2010;125(2 Suppl 2):S161–81. 5. Manning KD, Winawer NH, Murali MR. Allergy and anaphylaxis. In: McKean SC, Ross JJ, Dressler DD, et al, editors. Principles and practice of hospital medicine. McGraw-Hill; 2012. p. 1975–80. 6. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005; 95(3):217–26. 7. Anchor J, Settipane RA. Appropriate use of epinephrine in anaphylaxis. Am J Emerg Med 2004;22:488–90. 8. Lieberman P, Decker W, Camargo CA Jr, et al. SAFE: a multidisciplinary approach to anaphylaxis education in the emergency department. Ann Allergy Asthma Immunol 2007;98(6):519–23. 9. Arroabarren E, Lasa EM, Olaciregui I, et al. Improving anaphylaxis management in a pediatric emergency department. Pediatr Allergy Immunol 2011;22(7):708–14.
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