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SECTION X IMMUNE SYSTEM DISORDERS Allergic Disorders Aaron N. Barksdale and T. Paul Tran KEY POINTS • Allergy refers to inappropriate responses (hypersensitivity) by the host’s immune system. • Anaphylaxis is an acute, potentially fatal, systemic allergic reaction. Deaths in patients with anaphylaxis are caused by acute respiratory failure. • Foods, medications, and insect stings are the most common agents causing anaphylaxis. • Epinephrine is the first-choice medication in the treatment of anaphylaxis, with H1 and H2 antihistamines and steroids being helpful adjuncts. • Most cases of angioedema are mediated by IgE and respond to allergic therapy. Certain forms of angioedema, however, are mediated by bradykinin and may respond to new classes of medications, the kallikrein inhibitor (ecallantide) and C1 esterase inhibitor concentrates (Cinryze, Berinert). ALLERGIC DISEASE: ALLERGIC RHINITS, INSECT STINGS, DRUG ALLERGY EPIDEMIOLOGY The prevalence of allergic disorders, including the incidence of anaphylaxis, has been increasing worldwide in the last few decades and is a topic of intensive study.1,2 Features of Western lifestyles, such as changes in infant diets, widespread use of antibiotics, smaller family size, and cleaner child care, are believed to reduce stimulatory antigenic exposure in an individual’s early years. This has led to an environment in which the immune system is dominated by a persistent allergy-prone system.3 ALLERGIC RHINITIS It is estimated that up to 42% of Americans suffer from some form of allergic rhinitis at any one time,4 and it has been shown to have a strong correlation with asthma. In recent studies, nearly 40% of adults with allergic rhinitis were also found to have asthma, and 80% of asthmatics demonstrated signs of rhinitis. 106 INSECT STINGS Serious systemic reactions to insect stings are rare and occur in 1% of children and 3% of adults. Anaphylactic reactions account for approximately 50 deaths annually in the United States. There is a 2 : 1 male-to-female distribution, and adult male agricultural workers are considered the most vulnerable population. Individuals who experience large local reactions are less likely to have a systemic reaction (5% to 10%).5 DRUG ALLERGY A drug allergy is defined as an immune-mediated adverse response to a drug. An adverse drug reaction is defined as a noxious, unintended, or undesired response to a drug taken at a normal dose for the prevention, diagnosis, or treatment of a disease,6 and a drug side effect is an expected and known (adverse) effect of taking the drug that is not the intended therapeutic outcome. Although the true frequency is unknown, drug allergy is thought to account for approximately one third of adverse drug reactions.7 Adverse drug reactions affect 10% to 20% of hospitalized patients and more than 7% of the general population. PATHOPHYSIOLOGY The immune system protects the host by distinguishing self from nonself; it tolerates the former but attacks the latter.8,9 Allergy, allergic diseases, and hypersensitivity reactions arise when our immune system reacts inappropriately to allergens with resultant harm to the host.1,2,10,11 For allergic diseases to occur, predisposed individuals need to first be exposed to an allergen through a process called sensitization. The term atopy is used to describe the propensity in affected patients to produce IgE in response to otherwise innocuous environmental allergens. Atopic patients have higher serum levels of IgE antibody and a propensity for the development of one or more atopic diseases (e.g., allergic asthma, allergic rhinoconjunctivitis, atopic dermatitis, urticaria, angioedema). Hypersensitivity reactions are mechanistically divided into four types of reactions according to the Gell and Combs classification system (Box 106.1). The immediate hypersensitivity reaction (type I), which is mediated by IgE, serves as the classic model of the immune response to allergen. On initial exposure to allergen, T helper 2 (TH2) cells are activated, which results in the production of an array of cytokines that 917 SECTION X IMMUNE SYSTEM DISORDERS exert their effects on the T cells themselves, B cells, and antigen-presenting cells. IgE is elaborated and attached to the high-affinity Fc receptor on the surface of mast cells and basophils. Fixation of allergen-specific IgE leads to a series of cellular and molecular changes that prime these cells for future exposure. On reexposure, allergen cross-links the cellbound IgE on the surface of mast cells and basophils, thereby setting in motion a complex cascade of events that lead to the release of preformed mediators such as histamine, lipid mediators, and cytokines and subsequent activation of various inflammatory pathways. These mediators and products of secondary inflammatory pathways cause adherence and chemotaxis of inflammatory cells, increased capillary permeability, vasodilation, smooth muscle contraction, and sensory nerve stimulation. A few allergen molecules can thus cause the release of a large number of mediator molecules in a designed amplification response. Examples of type I hypersensitivity reactions include allergic rhinitis, allergic asthma, urticaria, angioedema, and anaphylaxis. See Box 106.1, Types of Hypersensitivity, online at www.expertconsult.com. and discharge (clear or can resemble strings of cheese); nasal congestion; itching of the nose; sneezing; rhinorrhea; and mild cough. Patients may report a temporal association with exposure to certain environment allergens (seasonal allergy, pollen, mold, animal dander). On physical examination, the nasal membranes are swollen with enlarged, pale turbinates and a clear nasal discharge. The maxillary sinuses may feel full and tender on palpation. INSECT STINGS (HYMENOPTERA VENOM ALLERGY) Patients with systemic allergic reactions from stings may exhibit generalized urticaria, angioedema, wheezing, stridor, anxiety, or other signs of respiratory and circulatory insufficiency. Most stings, however, cause self-limited local reactions consisting of redness, pain, and itching at the site of the sting. These reactions typically develop within minutes and usually last for a few hours. Local reactions rarely put patients at risk for future systemic reactions.5 Fire ant stings tend to produce pustulelike lesions. Local stings that result in subsequent swelling near the oropharynx (either cutaneous or deep) can cause airway compromise, and affected patients should be observed in the emergency department (ED) until the symptoms have resolved. Allergens are typically carbohydrate or protein molecules (or parts of a larger molecule) that elicit an immune response.10 The inflammation that occurs in allergy is divided into three temporal phases.10 Early-phase reactions occur within minutes of exposure and are considered immediate type I hypersensitivity reactions. Late-phase reactions typically occur within 2 to 6 hours and peak 6 to 9 hours after exposure. This response is thought to be due to newly synthesized cytokines, growth factors, and chemokines, which were released more slowly than the preformed mediators primarily responsible for the early-phase reaction. This reaction often involves airway narrowing and hypersecretion of mucus in the lungs, in addition to the erythema, warmth, and pain experienced in the skin. In some individuals there is no clinical distinction between the early and late phases. Chronic allergic inflammation is the final phase in the inflammatory process. It occurs after persistent or repetitive exposure to specific allergens and results in tissue remodeling and structural changes in affected cells. Chronic allergic inflammation can further increase epithelial injury, mucus production, and thickening of airway walls. The majority of serious sting-related reactions are caused by insects belonging to the order Hymenoptera (yellow jackets, hornets, honeybees, wasps, and fire ants).5 Their venom contains histamine, dopamine, various peptides, and protein enzymes that are either vasoactive or can elicit significant allergic reactions (IgE mediated). DRUG ALLERGY Most allergic reactions occur within 1 hour of taking the medication, and symptoms typically include urticaria, morbilliform rash, itching (lips, tongue, face), or sensitivity to light. Symptoms of anaphylaxis may also occur (see later in chapter). Late symptoms (1 to 2 weeks) include fever, muscle and joint aches, and swollen lymph nodes. PRESENTING SIGNS AND SYMPTOMS INSECT STINGS (HYMENOPTERA VENOM ALLERGY) Considerations include secondary bacterial infection, cellulitis, abscess, urticaria, angioedema, and anaphylactic reaction. Screening laboratory examinations for infection (complete blood count, wound culture) should be done if signs of infection are noted on physical examination. ALLERGIC RHINITIS A detailed history is important in making the diagnosis of allergic rhinitis. Patients often acknowledge a history of seasonal allergies (hay fever). Patients with allergic rhinitis frequently suffer from symptoms such as eye itching, swelling, 918 DIFFERENTIAL DIAGNOSIS AND MEDICAL DECISION MAKING ALLERGIC RHINITIS Box 106.2 lists other diagnostic considerations in patients with symptoms that may mimic allergic rhinitis.12 Patients older than 20 years should be investigated for nonallergic causes (e.g., polyps). Atopic patients with severely inflamed conjunctivae, lids, and periorbital structures should raise the possibility of atopic keratoconjunctivitis (Fig. 106.1) and vernal keratoconjunctivitis (Fig. 106.2). These two types of chronic allergic conjunctivitis have the potential to cause corneal erosions and ulcers leading to vision loss and should be managed in consultation with an ophthalmologist. Typically, no diagnostic tests need to be performed in the ED. Specific IgE serum assays such as the radioallergosorbent test (RAST), enzyme-linked immunosorbent assay (ELISA), skin prick test, and nasal smears are usually performed by allergists. CHAPTER 106 Allergic Disorders BOX 106.1 Types of Hypersensitivity Type I Hypersensitivity Immediate or immunoglobulin E (IgE)-mediated reaction: Binding of antigens to IgE on the surface of mast cells and basophils leads to the release of inflammatory mediators (maximal reaction in 20 minutes). This type of hypersensitivity reaction is seen with allergic diseases, drug reactions, urticaria or angioedema, and anaphylaxis. Type II Hypersensitivity Cytotoxic antibody reaction: Binding of antigens to their own cells (or foreign cells with foreign antigens) attracts binding by IgM/IgG antibodies, which subsequently causes injury and lysis of cells via the complement or mononuclear cell system. Type III Hypersensitivity Immune complex (IC)-mediated reaction: Binding of antigens to IgE forms soluble ICs, which are deposited on vessel walls and cause a local inflammatory reaction (Arthus reaction) by attaching to FγRIII receptors on inflammatory cells (maximum reaction, 4 to 8 hours). Type IV Hypersensitivity Cell-mediated delayed hypersensitivity reaction: Sensitized lymphocytes (TH1 cells) recognize the antigen and recruit additional lymphocytes and mononuclear cells to the site, thereby starting the inflammatory reaction. This type of hypersensitivity reaction is seen with contact dermatitis, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (maximum reaction, 48 to 72 hours). 918.e1 CHAPTER 106 Allergic Disorders BOX 106.2 Causes of Rhinorrhea and Nasal Obstruction Nonallergic Rhinitis with Eosinophilia Syndrome Nasal smears negative for allergens but with an abundance of eosinophils Mechanical Obstruction Foreign body Previous trauma involving the septum Polyps Adenoid disease Infectious Rhinosinusitis Primary or secondary bacterial, viral, or fungal infections Vasomotor Rhinitis Profuse, clear rhinorrhea and nasal congestion—may be triggered by environmental conditions such as cold air, odors, or changes in atmospheric pressure or by the ingestion of hot or spicy foods Drug Induced Includes entities such as rhinitis medicamentosa (rebound from prolonged use of topical decongestants) May be triggered by aspirin, nonsteroidal antiinflammatory drugs, or oral contraceptive use Systemic Disease Wegener disease, sarcoidosis Head trauma Modified from Greiner AN. Allergic rhinitis: impact of the disease and considerations for management. Med Clin North Am 2006;90:17-38. Fig. 106.1 Atopic keratoconjunctivitis. (From Baba I. Red eye—first aid at the primary level. Community Eye Health 2005;18:70-72.) DRUG ALLERGY Understanding the involvement of an immunologic mechanism in drug allergy may help physicians in determining whether a reaction represents an adverse drug reaction or a true drug allergy. For example, the stomach discomfort that may result from taking nonsteroidal antiinflammatory drugs (NSAIDs) is an adverse drug event and not a drug allergy. Factors that favor a drug allergy include a history of previous Fig. 106.2 Vernal keratoconjunctivitis. Notice the lumpy appearance on the conjunctivae. (From Yorston D, Zondervan M. Red eye picture quiz. Community Eye Health 2005;18:72-78.) sensitization (the drug was taken before) and typical allergic symptoms (urticaria, angioedema, wheezing). Common entities to consider are infection (viral exanthem, mononucleosis, Rocky Mountain spotted fever, syphilis, cellulitis, sepsis), insect bite, pityriasis rosea, serum sickness, vasculitides, contact dermatitis, fixed drug eruption, and drug hypersensitivity syndrome. Diagnosis of an adverse drug reaction relies on a careful history and thorough skin examination. A complete blood count, chemistry panel, and erythrocyte sedimentation rate may be ordered to evaluate possible infections or vasculitis. Skin testing is of limited value. RAST and ELISA for serum IgE require known immunogenic epitopes for the drugs, information that is usually unavailable. In cases of hemolytic anemia, the indirect Coombs test can be used to diagnose immune-mediated destruction of red blood cells. Studies show that 4.4% of patients whose penicillin allergy history was confirmed by a positive skin test experienced an allergic reaction to cephalosporins.13 Only 10% to 20% of patients who report a history of penicillin allergy are truly allergic when assessed by skin testing.14 Although the overall risk for a cross-allergic reaction to cephalosporins in patients with a history of a penicillin allergy is low, the use of cephalosporins requires weighing the risks versus benefits based on an informed discussion between the patient and treating physician. Table 106.1 shows the incidence of allergic reactions to penicillin.15 Some factors can transiently cause T cells to falsely identify the penicillin epitope as being allergic. For example, in up to half (50%) of patients with mononucleosis, a maculopapular rash develops after taking amoxicillin. These same patients often have no adverse drug reaction on subsequent challenge with amoxicillin at a later time. Penicillin allergy should not be diagnosed in such patients. TREATMENT ALLERGIC RHINITIS Oral second-generation H1 blockers (loratadine, fexofenadine), oral decongestants (pseudoephedrine), and nasal 919 SECTION X IMMUNE SYSTEM DISORDERS Table 106.1 Estimated Incidence of Allergic Reactions to Penicillin TYPE OF REACTION MANIFESTATION Late Rash Accelerated Immediate TIME OF OCCURRENCE AFTER FIRST DOSE PERCENTAGE OF PATIENTS SHOWING REACTION ≥72 hr 1.4 Urticaria 1-72 hr 0.3 Generalized urticaria 2-30 min 0.3 Anaphylaxis 2-30 min 0.04 Death from anaphylaxis 0.001 From Asthma and the other allergic diseases. NIAID Task Force Report, NIH Publ No. 79-387. Bethesda, MD: National Institutes of Health; 1979. decongestants (oxymetazoline, phenylephrine) can be used for mild, intermittent symptoms.16 Moderate to severe and persistent nasal symptoms may require the addition of intranasal steroid (fluticasone, triamcinolone, budesonide), or chromone derivative such as cromoglycate and nedocromil. An intraocular antihistamine (olopatadine), intraocular chromone, or intraocular ketorolac can be used for ocular allergies, including conjunctivitis.17 INSECT STINGS (HYMENOPTERA VENOM ALLERGY) The stinger should be removed if present. For minor local reactions, antihistamines and NSAIDs such as ibuprofen should be sufficient. Ice can be used to decrease the inflammation, and elevation will decrease the swelling. The pseudopustules caused by fire ant stings contain mostly necrotic material and should not be unroofed. These lesions should be managed similar to second-degree burns, with the therapeutic goal being pain control and minimization of the risk for secondary bacterial infection. Treatment of large local reactions includes cold compresses, NSAIDs, H1 antihistamines, and high-potency topical steroids. Prednisone (1 mg/kg or 60 mg orally) as a single dose or for 5 days might decrease local swelling. The swelling typically resolves in 7 to 10 days. Antibiotics should be prescribed only if signs of secondary bacterial infection are present. Coverage for methicillin-resistant Staphylococcus aureus should be considered. Management of systemic reactions to stings is similar to that for anaphylaxis. DRUG ALLERGY The most prudent approach in managing possible drug allergy–related complaints in the ED is to discontinue use of the suspect medication or medications, treat the allergic symptoms, and prescribe a suitable alternative drug or drugs. Severe symptoms should be treated in the same way as anaphylaxis (see Box 106.8). Patients with Stevens-Johnson syndrome and toxic epidermal necrolysis require a multidisciplinary approach that includes an intensivist, burn surgeon, and endocrinologist or allergist. For minor allergic drug reactions, H1 antihistamines can be prescribed for itching, flushing, and rash. Steroids are reserved for serious or extensive drug reactions. 920 FOLLOW-UP, NEXT STEPS IN CARE, AND PATIENT EDUCATION ALLERGIC RHINITIS Patients are advised to avoid allergens when practically feasible. Those who are sensitive to pollen should minimize time spent outdoors during periods of high pollen counts and lessen the allergen load indoors by keeping windows closed. Use of HEPA (high-efficiency particulate air) filters, infestation control (cockroach), and impermeable covers for mattresses and pillows may also decrease the severity of symptoms. INSECT STINGS (HYMENOPTERA VENOM ALLERGY) Patients with systemic reactions to stings warrant overnight observation in the hospital. Patients with limited or large local reactions can be managed as outpatients. Patients with urticaria or angioedema reactions should be referred to an allergist for possible skin testing and v enom immunotherapy. These patients should wear a MedAlert bracelet. Before discharge it is important that patients be educated about prevention of stings (always wearing shoes when outdoors and not wearing brightly colored clothes or fragrances in high-risk areas), the early signs of a systemic reaction, and how to self-administer an Epi-Pen. At least two Epi-Pens should be prescribed for emergency self-injection. DRUG ALLERGY The majority of patients with late (>1 hour to days) reactions to medications who have a mild to moderate rash can be safely discharged home. Those with immediate drug reactions (<1 hour) need to be observed in the ED. Patients with a systemic reaction whose symptoms resolve after a 4- to 6-hour observation period in the ED can be discharged home in the company of a family member. They should be prescribed two Epi-Pens, H1 antihistamines, a short course of steroids, and a Med-Alert bracelet. Patients at risk for a recurrent systemic drug reaction who have poor social support, comorbid conditions, and moderate to severe allergic syndromes warrant a hospital stay. At the end of the ED visit, patients should be educated about the nature of a drug allergy versus an adverse drug reaction. CHAPTER 106 URTICARIA EPIDEMIOLOGY Urticaria (hives) is a fairly common reaction that affects approximately 20% of the population at some point in their lifetime.18 It has numerous different underlying causes and consists of several different types and subtypes. Spontaneous urticaria is broadly divided into acute (<6 weeks) and chronic (≥6 weeks) forms, with the latter representing approximately 10% to 20% of cases. PATHOPHYSIOLOGY The classic wheal lesions associated with urticaria are the result of edema within the mid and upper dermal layers of the skin. Dilation of lymphatic vessels and capillary venules allows extravasation of protein-rich fluid into the surrounding tissue. This complex inflammatory process involves a variable mixture of macrophages, T cells, neutrophils, eosinophils, and mast cells.19 PRESENTING SIGNS AND SYMPTOMS Patients with urticaria usually have hives of variable duration and location.20,21 Urticarial lesions are pruritic, erythematous, raised rashes that blanch on palpation. The lesions are typically round or oval with serpiginous borders, but they may vary in color, size, and shape (Fig. 106.3). They may be localized or appear throughout the body, but there is a slight predilection for the trunk, hands, feet, lips, tongue, and ears. Urticaria usually starts with erythema (flare) as a result of capillary vasodilation in the superficial layer of the dermis. As the protein-rich fluid extravasates into surrounding tissue, it evolves into raised wheals and may change from red to white. A history of pruritic red rash that changes in size and Allergic Disorders shape, with extension and regression over a period of hours or days, favors the diagnosis of urticaria. DIFFERENTIAL DIAGNOSIS AND MEDICAL DECISION MAKING The first step in narrowing the differential diagnosis of urticaria is to determine whether the urticaria is acute (<6 weeks of symptoms) or chronic (≥6 weeks of symptoms).20,21 The differential diagnosis of urticaria is outlined in Box 106.3 and illustrated in Figure 106.4. See Box 106.3, Differential Diagnosis of Urticaria, online at www.expertconsult.com Evaluation of acute urticaria and angioedema is based on a careful history and skin examination; little additional laboratory testing should be needed. The work-up for chronic urticaria is usually performed by an allergist in the office. TREATMENT Therapy for acute urticaria includes avoidance of the suspected causative agent and administration of H1 antihistamines (see Fig. 106.4). The second-generation H1 antihistamines (cetirizine, loratadine, fexofenadine, desloratadine) are currently recommended as the first-line drugs.18,20 For urticaria judged difficult to control with antihistamines alone, prednisone can be added.20 If the urticarial rash is extensive and pruritus is severe, epinephrine can be administered (0.3 to 0.5 mL of a 1 : 1000 dilution intramuscularly). It may be repeated every 1 to 2 hours as needed. Caution is advised when administering epinephrine to patients at risk for coronary heart disease (>35 years of age, other risk factors for coronary artery disease). Patients with chronic urticaria can be prescribed a nonsedating H1 antihistamine (in higher dosages) as a temporizing measure and be referred to an allergist for further care. FOLLOW-UP, NEXT STEPS IN CARE, AND PATIENT EDUCATION Most patients with urticaria (acute and chronic) can be managed as outpatients. Usually, a 7-day course of a secondgeneration H1 antihistamine is sufficient, although a corticosteroid (prednisone) in a tapering course is sometimes added for moderate to severe cases. ANGIOEDEMA EPIDEMIOLOGY Fig. 106.3 Acute urticaria. (Copyright 2001–03, Johns Hopkins University School of Medicine. Shahbaz Janjua: Dermatlas. Available at http://www.dermatlas.org. With permission.) Angioedema (not including hereditary angioedema [HAE]) may affect 10% to 20% of the population at some time in 921 CHAPTER 106 Allergic Disorders BOX 106.3 Differential Diagnosis of Urticaria Foods, Additives Seafood (fish, shellfish, scombroid), tree nuts, eggs, seeds Foods containing allergens that are cross-reactive with latex, including bananas, avocados, kiwi fruit, chestnuts Food preservatives such as tartrazine, benzoates, and sulfites Other: cow’s milk, pork, strawberries, wheat, chocolate, tomatoes Medications IgE mediated: penicillins, sulfonamides, cephalosporins Nonimmunologic release of histamine: acetylsalicylic acid, nonsteroidal antiinflammatory drugs, indomethacin, angiotensinconverting enzyme inhibitors, morphine, codeine, acetylcholine, iodinated contrast dye, beta-blockers, vancomycin Infections Viral infections: Epstein-Barr virus, hepatitis, coxsackievirus Bacterial (occult) infections: sinusitis, dental infections or abscesses, chronic cholecystitis Fungal infections: candidiasis, dermatophytosis Parasitic infections Systemic Disease Rheumatologic or immunologic: vasculitis, serum sickness, systemic lupus erythematosus, juvenile rheumatoid arthritis Endocrinologic: thyroid (both hyperthyroid and hypothyroid) disease, progesterone dermatitis, pruritic urticarial papules and plaques of pregnancy, premenstrual flare-up Skin disease: mastocytosis, dermatitis herpetiformis, amyloidosis, pemphigoid Neoplastic: paraneoplastic syndrome, Hodgkin disease, leukemia Inhalants Pollen Animal dander House mite dust Mold spores Household chemicals, aerosols Hymenoptera Yellow jackets, honeybees, hornets, wasps most commonly reported; fire ants Types of Urticaria Dermatographism: may begin suddenly after a viral illness or drug therapy Pressure or vibratory urticaria: caused by tight clothing around the waist (may be misdiagnosed as scabies) Heat urticaria: may be caused by a rise in core temperature after a hot bath, fever, vigorous exercise (also known as cholinergic urticaria because it can be induced by injection of a cholinergic agent) Cold urticaria: caused by exposure to cold temperatures Solar urticaria: occurs after exposure to intense sunlight or artificial light (antigens produced in the skin may interact with immunoglobulin E) Water urticaria: prickling skin sensation without skin lesions within 15 minutes of contact with water Exercise urticaria: may progress to anaphylaxis Household chemicals, aerosols Contact urticaria: urticarial wheals or hives develop within 30 to 60 minutes after cutaneous exposure to certain agents, including plants (nettles), animals (caterpillars, jellyfish), latex, cosmetics, and various chemicals Modified from Dibbern Jr DA. Urticaria: selected highlights and recent advances. Med Clin North Am 2006;90:187-209. 921.e1 SECTION X IMMUNE SYSTEM DISORDERS History and skin examination consistent with urticaria <6 weeks ≥6 weeks Chronic urticaria Acute urticaria 1. Review history • Food and drink • New medications • Environmental allergens (e.g., plants, animals, cosmetics, history of travel) • Insect bite • Serum sickness causes • Physical urticaria (exercise, heat, cold, solar) • Constitutional symptoms c/w a viral/bacterial/ fungal infection 2. Physical examination • Wheals and flares (evanescent) • Signs of infection 3. Management • 2nd-generation antihistamine • H2 blocker • Epinephrine in selected cases (see text) • Steroids in selected cases (see text) • Primary care physician referral 1. Review history • Food and drink (food additives, dyes) • Medication (ASA, NSAIDs) • Physical urticaria (exercise, heat, cold, solar) • Constitutional symptoms (e.g., weight gain, fever, fatigue) 2. Physical examination • Fixed wheals and flares • Signs of occult infection 3. Management • Allergist referral • 2nd-generation antihistamine • Doxepin, 25 mg qid • Steroids—indicated for angioedema-urticariaeosinophilia syndrome • Other screening examinations for consultants (see text) Fig. 106.4 Algorithm for the diagnosis and treatment of urticaria. ASA, Acetylsalicylic acid; c/w, consistent with; NSAIDs, nonsteroidal antiinflammatory drugs. their lives; most chronic angioedema is idiopathic. HAE is an autosomal dominant genetic disorder with an estimated prevalence of 1 per 10,000 to 150,000 persons. The incidence of angiotensin-converting enzyme inhibitor (ACEI)-associated angioedema is approximately 0.2% to 0.7% and slightly higher in the African American population. Episodes have been reported to occur within days of initiating ACEI therapy and up to 8 years later, with an average onset of approximately 10 months. Ten percent to 25% of cases of angioedema encountered in the ED are considered to be life-threatening. African Americans are more susceptible to angioedema induced by ACEIs. Other forms of angioedema have no clear association between race and the frequency or severity of the disease. In HAE, affected women tend to have more frequent attacks and a more severe clinical course. Chronic idiopathic angioedema is more common in females than in males. Angioedema can affect patient of all ages. For patients with HAE, the onset of symptoms is often around puberty. Idiopathic angioedema is more common in those aged 30 to 50 years than in other age groups. Patients typically experience minor swelling in childhood that may go unnoticed, with increased severity noted around puberty. However, type III HAE is found in the second decade of life or later and occurs only rarely before puberty. Five percent of adult HAE carriers are asymptomatic and identified only after their children are found to be symptomatic. Urticaria-associated angioedema occurs in nearly 50% of children with urticaria. Because urticaria occurs in 2% to 3% 922 of children, urticaria-associated angioedema is estimated to occur in 1% to 2% of the general population. PATHOPHYSIOLOGY Angioedema (swelling) refers to vasodilation and edema in the lower dermis and subcutaneous layers of the skin.22 In the majority of cases angioedema shares a similar allergic mechanism, but in selected cases it is the result of a reaction mediated by bradykinin. Both forms of angioedema can appear similar clinically, with bradykinin-mediated angioedema typically being manifested as angioedema without urticaria. They both commonly affect the eyelids, face, lips, and tongue and can potentially cause life-threatening respiratory compromise. It is important to distinguish the two forms because bradykininmediated angioedema may respond better to the new classes of medications, including recombinant C1 factor, kallikrein inhibitor, or a bradykinin receptor antagonist. Bradykinin-mediated angioedema typically falls into one of two groups, HAE or acquired angioedema (AAE). HAE was first described by William Osler in 1888. It is a rare autosomal dominant disorder with an overall incidence of 1 in 50,000.23 Approximately 25% of cases are the result of a spontaneous mutation. HAE has three subtypes. Type I (85%) is characterized by low levels of C1 esterase inhibitor (C1 INH), type II (<15%) consists of normal but poor functioning levels of C1 INH, and type III (rare) has normal C1 INH levels CHAPTER 106 and activity but probably involves another unidentified defect or gene mutation at the receptor level. Currently, bradykinin is thought to be the primary molecule responsible for angioedema in patients with HAE. Documented triggers include infection, stress, trauma, oral contraceptives, pregnancy, and menstruation.23 AAE comprises a heterogeneous group that includes druginduced, idiopathic, and environmental agent–related angioedema and acquired C1 INH deficiency (ACID). ACID is characterized by a lack of inheritance and low-level or nonfunctional C1 INH. Drug-induced angioedema is most commonly caused by ACEIs.24 Up to 50% of those who still take an ACEI after an episode of angioedema will experience recurrent episodes. Discontinuation of the medication results in resolution of the symptoms in the majority of patients (within 24 to 48 hours). ACEIs block the degradation of kinins and thereby lead to elevated levels of bradykinin and other peptides. This results in vasodilation and tissue edema of the deeper layers of the skin, which is clinically manifested as angioedema.24 PRESENTING SIGNS AND SYMPTOMS Angioedema has a brawny appearance and occurs when extravasation of fluid occurs at the subcutaneous and deep dermal layers of the skin. Patients with angioedema experience less pruritus than urticaria and often complain of a pain or burning sensation at affected sites. Angioedema also tends to involve the face, tongue, lips, and larynx but can occur in the mucosal layer of the gastrointestinal tract and genitalia in men. Involvement of the gastrointestinal tract can cause nausea, vomiting, diarrhea, and abdominal pain. HAE is usually manifested in the second decade of life and appears either alone or with urticaria. Recurrent angioedema without urticaria later in life (e.g., middle age) may suggest some form of AAE, including ACID- and ACEI-induced angioedema (if undergoing ACEI therapy). Both HAE and ACEI-induced angioedema tend to have a predilection for the face, tongue, lips, oropharynx, and larynx. Patients with HAE may complain of a lump or tightness in the throat and progressive dyspnea. Physical examination may reveal hoarseness, inspiratory stridor, and rarely, urticaria. Prompt attention to airway management can be lifesaving. After stabilization, these patients need to be identified and referred to an allergist for further work-up and treatment. DIFFERENTIAL DIAGNOSIS AND MEDICAL DECISION MAKING When angioedema is suggested by the history and physical examination, it is important to determine whether it is associated with other allergic findings, urticaria, a family history, or other medications (ACEIs). The differential diagnosis of angioedema is outlined in Box 106.4. Patients suspected of having HAE should first have their complement 4 (C4) and complement 2 (C2) levels checked. As recommended by the consulting allergist or internist, other tests can include a CH50 (total complement activity) test, C1 INH test, or C1 functional assay. Additional screening tests may be considered to help rule out occult infection, Allergic Disorders BOX 106.4 Differential Diagnosis of Angioedema Cellulitis, erysipelas Acute contact dermatitis Crohn disease (of the mouth and lips) Dermatomyositis Venous obstructive disease (superior vena cava syndrome) Heart failure Photodermatitis Tumid discoid lupus erythematosus Melkersson-Rosenthal syndrome Ascher syndrome Facial lymphedema Renal disease From Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol 2005;53:373-88. hematologic or oncologic pathology, and rheumatologic or inflammatory disorders, which may aid the consultant in subsequent evaluation of these patients. TREATMENT The first priority in the management of patients with acute angioedema is to secure a patent airway if needed.22,23 Endotracheal intubation should be considered early in patients with progressive laryngeal edema. As soon as the patient is situated, intravenous access should be established, oxygen administered, and the patient placed on a monitor. The majority of cases of angioedema are type I hypersensitivity reactions. If signs of airway compromise or hypoxia are present, epinephrine should be administered (0.3 to 0.5 mL of a 1 : 1000 dilution intramuscularly) and repeated every 5 minutes as needed. Nebulized racemic (or regular) epinephrine (0.5 mL of a 2.25% racepinephrine solution; multiple doses are acceptable in patients without intravenous access) can be a temporizing measure for pharyngeal and laryngeal edema before or in addition to parenteral administration of epinephrine. In patients with mild symptoms and no airway involvement, H1 and H2 antihistamines should be used first. Parenteral steroids (methylprednisolone, 125 mg intravenously) should be administered for moderate to severe attacks. Epinephrine, antihistamines, and corticosteroids are generally ineffective in the treatment of HAE and ACEI-induced angioedema, although they are commonly given in the acute setting. The use of new drugs for acute HAE attacks and ACEI-induced angioedema is still in the formative stage. Plasma-derived C1 INH concentrate (Berinert, 20 U/kg intravenously, Cinryze, 1000 units intravenously) is currently available in the United States.15 Ecallantide, a kallikrein inhibitor (30 mg subcutaneously in adults), is another recent agent approved by the Food and Drug Administration for the treatment of acute HAE. Aminocaproic acid, tranexamic acid, and anabolic androgens (danazol, stanozolol) are often prescribed for HAE prophylaxis but may be considered for the treatment 923 SECTION X IMMUNE SYSTEM DISORDERS of acute episodes. Additional treatment alternatives include solvent detergent–treated plasma or fresh frozen plasma, although these therapies are considered less safe.23 FOLLOW-UP, NEXT STEPS IN CARE, AND PATIENT EDUCATION Patients with mild symptoms who improved clinically after treatment and were observed for 4 to 6 hours in the ED can be discharged home with H1 antihistamines and a short course of steroids. If the patient was taking an ACEI, its use should be stopped. Replacement candidates include calcium channel blockers and thiazides. Angiotensin receptor blockers are deemed acceptable by some authorities because the risk for angioedema from these agents is considered acceptably low.24,25 Beta-blockers are not advised in the initial setting because of the theoretic risk of exacerbating the angioedema and potential antagonistic effects with epinephrine. Inpatient admission is warranted for those with moderate to severe symptoms who fail to display signs of resolution after 4 to 6 hours in the ED. In particular, patients with HAE should be managed in consultation with their primary physician or allergist. Most of these patients, especially those with face and laryngeal involvement, warrant observation overnight in the hospital. ANAPHYLAXIS EPIDEMIOLOGY Anaphylaxis is a life-threatening systemic hypersensitivity reaction that is rapid in onset and usually precipitated within minutes of exposure to an allergen. Because of lack of data the true incidence of anaphylaxis is unknown, but recent evidence suggests that it is increasing and its incidence may be as high as 2%.26,27 Risk factors for anaphylaxis include atopy, higher socioeconomic status, northern locations, female sex (adults), and route of allergen exposure. An individual with a history of asthma is more likely to experience a severe or fatal reaction.27 TRIGGERS Foods, predominantly peanuts, tree nuts, shellfish, fish, eggs, soy, and cow milk, are the most common cause of anaphylaxis and are responsible for up to 30% of all fatal cases. Insect stings, primarily by those belonging to the order Hymenoptera, are the second most common cause of anaphylaxis. They account for approximately 18.5% of anaphylactic cases. Medications are the third most common cause of anaphylaxis (13.7%). Although the β-lactams (penicillin) are commonly involved, several other drugs are known to cause anaphylaxis, including NSAIDs, aspirin, protamine, vancomycin, neuromuscular blocking agents, and newer biologic modifiers such as omalizumab, infliximab, and cetuximab.27,28 Although the three groups just mentioned (foods, stings, and drugs) are responsible for the majority of anaphylactic reactions, other prominent triggers of anaphylaxis include latex, seminal fluid, transfusion products, allergen immunotherapy, contrast dye, methylmethacrylate (bone cement), and 924 physical activity (exercise). Exercise-induced anaphylaxis is noteworthy because its pathophysiology is unknown. Some authorities suspect co-triggers, such as a specific food, drug, or recent high pollen exposure as the actual culprit.29 In approximately 20% of anaphylactic cases, no identifiable triggers are found, and the reaction is termed idiopathic anaphylaxis.30 PATHOPHYSIOLOGY Anaphylaxis is commonly an IgE-mediated type I hypersensitivity reaction, but it can also occur through other immunologic mechanisms or direct mast cell activation (formerly known as an anaphylactoid reaction). The resultant degranulation of mast cells and basophils causes the release of preformed mediators such as histamine, tryptase, carboxypeptidase A3, chymase, and tumor necrosis factor-α, as well as newly generated mediators such as leukotrienes, prostaglandins, cytokines, and platelet-activating factor. These vasoactive molecules together are believed to be responsible for the pathophysiology of anaphylaxis. Of these mediators, histamine is probably the most important. It mediates systemic vasodilation and increases vascular permeability, cardiac contractility, and glandular secretion. The leukotrienes, together with platelet-activating factor, contribute to vascular permeability and, in combination with prostaglandins (D2), cause bronchoconstriction. PRESENTING SIGNS AND SYMPTOMS Anaphylaxis is a systemic reaction of rapid onset that involves multiple organ systems, principally the cutaneous, respiratory, cardiovascular, gastrointestinal, and central nervous systems (Box 106.5).31 Patients may initially experience warmth and tingling of the face, mouth, and chest, followed by nasal congestion, sneezing, and ocular itching and tearing. Urticaria, pruritus, and angioedema occur roughly 90% of the time. The majority of anaphylactic reactions become clinically evident within minutes after parenteral exposure (average of 5 to 30 minutes), with a longer latent time (2 hours) after the ingestion of a triggering agent. In general, the sooner the clinical syndrome is manifested after exposure to the allergen, the more severe the reaction. Most fatalities occur within the first 30 minutes after exposure. In the setting of shock, cutaneous symptoms may be absent as a result of compensatory vasoconstriction. Anaphylaxis may precipitate an acute coronary syndrome in what is known as cardiac anaphylaxis.32 More commonly in the elderly, the initial complaint may be abdominal pain and cramping. In approximately 20% of patients, anaphylaxis may recur 1 to 72 hours after apparent clinical resolution of all signs and symptoms in what is called a biphasic reaction.33 There is currently no evidence or expert consensus on clinical predictors of the occurrence of a biphasic anaphylactic reaction, although it has been suggested that a biphasic reaction is rare in patients without hypotension and airway obstruction during the initial evaluation.34 Most authorities recommend an observation period (8 to 24 hours) after the initial mani festation to minimize the untoward effects of the biphasic reaction.33 CHAPTER 106 BOX 106.5 Common Clinical Findings in Patients with Anaphylaxis Cutaneous, Subcutaneous, Mucosal Tissue Urticaria (hives), angioedema, flushing, pruritus, morbilliform rash, pilar erection Conjunctival erythema, tearing Pruritus and swelling of the lips, tongue, uvula/palate Pruritus of the genitalia, palms, soles Respiratory Nasal congestion, rhinorrhea, sneezing Throat tightness and soreness, dysphonia and hoarseness, dry staccato cough, stridor, dysphagia Dyspnea, chest tightness, deep cough, wheezing, bronchospasm Gastrointestinal Nausea, vomiting (stringy mucus), dysphagia, cramping abdominal pain, diarrhea Cardiovascular Chest pain, palpitations, tachycardia, bradycardia, or other dysrhythmia Dizziness, altered mental status, hypotension, shock Central Nervous System Aura of impending doom, uneasiness, throbbing headache, dizziness, confusion, tunnel vision Infants and children: sudden behavioral changes, such as irritability, cessation of play, and clinging to parent Other Metallic taste in the mouth Uterine contractions in postpubertal female patients Modified from Simons FE. Anaphylaxis. J Allergy Clin Immunol 2010; 125(Suppl 2):S161-81 (with permission). DIFFERENTIAL DIAGNOSIS AND MEDICAL DECISION MAKING The clinical spectrum of anaphylaxis overlaps that of several other syndromes, especially those involving the skin and cardiorespiratory system (Box 106.6). Vasovagal reactions may mimic early anaphylaxis, although these patients usually have bradycardia, hypotension, diaphoresis, and pallor, as opposed to the tachycardia, hypotension, diaphoresis, and urticaria usually associated with anaphylaxis. Anaphylactic shock may also appear clinically indistinguishable from other forms of shock (distributive, septic, or cardiogenic). The acute onset and characteristic angioedematous urticarial rash favor the diagnosis of anaphylactic shock. Flushing syndromes also frequently mimic anaphylactic reactions. They may be associated with dry skin or diaphoresis and are the result of numerous different drugs, ingestants, and other physiologic syndromes. Anaphylaxis is diagnosed clinically. The diagnosis is considered highly likely when any of three clinical criteria in Box 106.7 are met.35 Currently, histamine and tryptase are the only measurable markers of anaphylaxis in clinical laboratories.31 Histamine plasma levels become elevated approximately 10 minutes after the onset of symptoms and remain so for up to an hour. Allergic Disorders BOX 106.6 Differential Diagnosis of Anaphylaxis Flush Syndromes Hereditary angioedema Urticaria vasculitis Carcinoid syndrome Systemic mastocytosis Urticaria pigmentosa Vasoactive intestinal polypeptide–secreting tumors Medullary carcinoma of the thyroid Pheochromocytoma Acute alcohol syndrome Monosodium glutamate toxicity Sulfites Scombroidosis Infections, Respiratory Syndrome Epiglottitis, supraglottitis Retropharyngeal, peritonsillar abscess Laryngeal spasm, foreign body aspiration, tumor Acute asthma exacerbation, chronic obstructive pulmonary disease Shock Syndromes Hemorrhagic Cardiogenic Septic Spinal shock Somatoform, Psychogenic Panic attacks Munchausen, factitious disorder Somatoform idiopathic anaphylaxis Miscellaneous Idiopathic Vasodepressor (vasovagal) reactions Progesterone anaphylaxis Red man syndrome (vancomycin) Capillary leak syndrome Peak levels of serum tryptase occur between 60 and 90 minutes and persist for as long as 6 hours. These markers must be determined within the time frames mentioned and may be helpful when it is uncertain whether anaphylaxis has occurred. It should be noted that food-induced anaphylaxis may not be accompanied by elevated levels of tryptase. Additional laboratory tests and imaging may be necessary to help rule out other disease processes. TREATMENT Early administration of epinephrine is the mainstay of treatment of anaphylaxis (Box 106.8). It should be administered quickly and preferably intramuscularly in the lateral aspect of the thigh (vastus lateralis). Epinephrine should be considered if anaphylaxis is suspected even when only one system (e.g., skin) is involved. Doses can be repeated every 5 to 10 minutes or more frequently as indicated clinically.27,31 Caution should be exercised in patients with risk factors for ischemic heart disease, although there are no absolute contraindications to epinephrine in those initially seen in anaphylactic shock. 925 SECTION X IMMUNE SYSTEM DISORDERS BOX 106.7 Clinical Diagnosis of Anaphylaxis Anaphylaxis is highly likely when any of the following three criteria are fulfilled: 1. Acute onset (minutes to hours) of an illness with cutaneous or mucosal involvement AND at least one of the following: a. Respiratory compromise (e.g., dyspnea, wheezing/ bronchospasm, stridor, hypoxia) b. Reduced blood pressure or symptoms of end-organ dysfunction 2. Two or more of the following occurring rapidly after exposure to a probable allergen (minutes to several hours): a. Involvement of skin or mucosal tissue b. Respiratory compromise c. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 3. Reduced blood pressure after exposure to a known allergen for that patient (age specific, less than 90 mm Hg, or 30% decline from baseline) Reproduced from Sampson HA, Munoz-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. Ann Emerg Med 2006;47:373-80. Intravenous infusion should be used only in patients who remain hypotensive and have failed to respond to multiple intramuscular injections.27,31 Inhaled epinephrine may be used as adjunctive therapy for laryngeal edema but should never replace the intramuscular or intravenous route (Fig. 106.5). In conjunction with the administration of epinephrine, the patient should be placed in the supine position with the lower extremities elevated. Intravenous access should be established, supplemental oxygen administered, and the patient placed on a monitor. Patients with rapidly progressive respiratory insufficiency will benefit from early endotracheal intubation. Use of rapid-sequence intubation should be approached with great caution because of the potential for rapid deterioration of the oral and laryngeal edema. Plans for backup airway support and rescue airway devices, including a surgical airway, may be prudent. Hypotension is treated aggressively with crystalloid infusion and colloid as indicated clinically. Caution should be taken in patients with a history of congestive heart failure. Patients with persistent hypotension despite appropriate doses of epinephrine and intravenous fluid resuscitation should be administered vasopressors drips (see Box 106.8). H1 antihistamine (diphenhydramine) should be given to improve the itching and hives in patients with anaphylaxis. H2 antihistamines (ranitidine, cimetidine) have a synergistic effect with H1 antihistamines and should be given because BOX 106.8 Treatment Options for Anaphylaxis General Two large-bore intravenous lines (intraosseous if unable to acquire intravenous access) Placement of the patient on a monitor Supplement oxygen (nasal canula, non-rebreather mask) Consideration of a tourniquet—if anaphylaxis is due to an insect sting at the distal end of an extremity (blood pressure cuff inflated to approximately 20 mm Hg greater than systolic blood pressure), release every 10 minutes for 1 minute or when the symptoms resolve Epinephrine Intramuscular (subcutaneous acceptable)—1 : 1000; adult: 0.3 to 0.5 mL every 5 minutes as necessary, titrated to effect; pediatric: 0.01 mL/kg every 5 minutes as necessary, titrated to effect) Alternatively, EpiPen (0.3 mL) or EpiPen Jr (0.15 mL) can be administered into the anterolateral aspect of the thigh; removal of clothing unnecessary Intravenous infusion—1 : 100,000; 0.1 mL of a 1 : 1000 dilution in 10 mL of normal saline (NS), 100 mcg, over a 10-minute period; equivalent to 10 mcg/min for a 10-min period, titrated to effect; repeat as necessary; continuous hemodynamic monitoring required Continuous infusion—1 mL of a 1 : 1000 dilution of epinephrine in 250 mL of 5% dextrose in water (D5W) results in a concentration of 4 mcg/mL; can be started at 1 mcg/min and increased to 4 mcg/min if needed Pediatric continuous infusion—rate of 0.1 mcg/kg/min (up to 30 kg) advised, with increasing increments of 0.1 mcg/kg/ min to a maximum of 1.5 mcg/kg/min 926 Second-Line Medications Antihistamines Diphenhydramine (IV or PO)—adult: 50 to 100 mg, up to 400 mg/24 hr, titrated to effect; pediatric: 0.02 mg/kg, up to 300 mg/24 hr, titrated to effect Ranitidine or other H2 blocker (IV or PO)—adult: 50 mg IV, 300 mg PO (4 mg/kg); pediatric: 1 mg/kg Aerosolized Beta-Agonists and Others Albuterol—adult: 2.5 mg; pediatric: 0.02 mL/kg up to 2.5 mg in 3 mL of NS; may be given continuously Ipratropium—adult: 0.5 mg; pediatric: 0.25 mg in 3 mL of NS; repeat as necessary Prednisone Adult: 40 to 60 mg PO; pediatric: 1 to 2 mg/kg PO Methylprednisolone Intravenous infusion—adult: 125 to 250 mg; pediatric: 40 to 80 mg Glucagon Intravenous infusion—adult: 1 to 5 mg over a 5-minute period; pediatric: 0.5 mg, followed by 5 to 15 mcg/min as drops (gtt); for refractory hypotension or patients receiving beta-blockers Dopamine Intravenous infusion—5 to 20 mcg/kg/min gtt, and/or dobutamine, 5 to 20 mcg/kg/min gtt Norepinephrine Intravenous infusion—8 to 12 mcg/min gtt (2 to 3 mL/min; 4 mg added to 1000 mL of D5W provides a concentration of 4 mcg/mL) CHAPTER 106 they improve vascular permeability, flushing, gastric secretion, and mucus production in the airway. Antihistamines, however, should be considered second-line agents after epinephrine. Inhaled β-agonists (albuterol) can be administered for bronchospasm refractory to appropriate doses of epinephrine. Glucocorticosteroid provides no immediate benefit in the acute treatment of anaphylaxis, although it may be helpful in preventing biphasic reactions. SPECIAL CONSIDERATIONS PATIENTS TAKING BETA-BLOCKERS Patients currently taking beta-blockers may not respond adequately to epinephrine and intravenous fluids. A glucagon Possible anaphylaxis BOX 106.9 Standard Pharmacologic Treatment Protocol for Patients with a History of Radiocontrast-Induced Anaphylaxis Prednisone, 50 mg PO given 13 hours, 7 hours, and 1 hour before the procedure Diphenhydramine, 50 mg IM given 1 hour before the procedure Consider giving an H2 antagonist, such as ranitidine, 300 mg PO as drops 3 hours before the procedure Modified from Lieberman P. Anaphylaxis. Med Clin North Am 2006; 90:77-95. RED FLAGS • Remove any triggering agent • Place patient in Trendelenburg position if hypotensive • Check airway, breathing, circulation, vital signs • Racemic epinephrine, 0.5 mL of 2.25% solution in 2.5 mL of NS via nebulizer while awaiting definitive airway management; can repeat multiple times • Establish large-bore IV catheters • Pulse oxymetry; cardiac monitoring/ECG; portable CXR; blood draw • Place a loose tourniquet proximal to the reaction site; if reaction site on extremity, place extremity in dependent position • Administer epinephrine. Inject 0.1-0.2 mL 1 : 1000 epinephrine SQ locally to the reaction site • Provide O2, nebulized β-agonist; IV access with NS wide open; put patient on monitor • Antihistamines, H2-blocker, steroids Improved Not improving/ deteriorating • Observe in ED for 6 hours • Review medications • Provide definitive airway control • Repeat 0.3 mL 1 : 1000 epinephrine IM every 10-15 minutes, up to 5 doses • Infuse crystalloid/colloid if hypotensive (saline, lactated Ringer solution, hydroxyethyl starch, 5% albumin); titrate to blood pressure • Consider pulmonary artery catheter, other diagnosis • Consider IV epinephrine gtt, glucagon, vasopressors Discharge from ED Allergic Disorders ICU Fig. 106.5 Treatment algorithm for possible anaphylaxis (see Box 106.8 for drug dosages and indications). CXR, Chest radiograph; ECG, electrocardiogram; ED, emergency department; gtt, drops; ICU, intensive care unit; IM, intramuscularly; IV, intravenous; NS, normal saline; SQ, subcutaneously. Management of Anaphylaxis Failure to diagnose anaphylaxis early or to recognize the need to secure the airway early Delayed administration of epinephrine Incorrect administration of intravenous epinephrine (e.g., not diluting it, wrong concentration) infusion should be strongly considered in these cases (see Box 106.8).27,31 Conversely, these patients may also demonstrate unopposed α-adrenergic effects after epinephrine administration and may require an alpha-blocker such as phentolamine. PATIENTS WITH ALLERGY TO INTRAVENOUS CONTRAST MEDIA Pretreatment with antihistamines and steroids significantly decreases the frequency and severity of anaphylactoid reactions in patients who have sustained a previous reaction to intravenous radiocontrast media. Each hospital has its own pretreatment protocols for clinical procedures; Box 106.9 reproduces one such protocol.36 FOLLOW-UP, NEXT STEPS IN CARE, AND PATIENT EDUCATION Patients who experience complete resolution of symptoms and were never hypotensive can potentially be discharged home. Although the time frame for biphasic reactions varies significantly, limited literature suggests that patients be observed in the ED for up to 8 hours.33 Oral H1 antihistamines such as diphenhydramine (50 mg every 6 hours for 72 hours) and H2 blockers such as ranitidine (150 mg every 12 hours for 72 hours) along with oral prednisone may prevent possible relapse.37 These patients should be instructed to return to the ED if they experience any recurrent symptoms consistent with their previous anaphylactic reaction. All patients who have experienced an anaphylactic or significant allergic reaction should be prescribed at least two 927 SECTION X IMMUNE SYSTEM DISORDERS TIPS AND TRICKS Prevention of Anaphylaxis and Anaphylactic Death Obtain a thorough drug allergy and atopic history. Check all drugs for proper labeling. Give drugs orally rather than parenterally when possible. Give drugs in distal end of the extremity if possible when a parenteral route is necessary. Always have resuscitation equipment available when administering antigenic compounds. Ensure that patients remain in the emergency department for at least 30 minutes after drug administration. Use unrelated drugs when feasible in susceptible patients. Encourage patients to carry warning identification (MedicAlert, wallet ID). Educate patients on the technique of self-injection of epinephrine and urge them to carry the treatment kit at all times. Instruct patients to avoid known antigens (stinging insects, foods, antibiotics). Refer patients to an allergist for a skin test and possible immunotherapy. 928 Epi-Pens, one kept at the common residence and another in the purse or briefcase. In addition, patients should be taught how to self-administer it. Predisposed patients should be encouraged to wear a Medic-Alert bracelet or carry a wallet card identifying their hypersensitivity. Patients should also be referred to an allergist for possible skin testing and hyposensitization immunotherapy. Hospital admission should be considered for patients who show slow clinical improvement, were hypotensive, and had upper airway involvement or persistent bronchospasm. Patients at risk for a biphasic reaction, such as those maintained on chronic beta-blocker therapy, may also be candidates for extended observation in the hospital. REFERENCES References can be found www.expertconsult.com. on Expert Consult @ CHAPTER 106 REFERENCES 1. Kay AB. Allergy and allergic diseases. Second of two parts. 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