Chapter 86. Anaphylactic Reactions and Anesthesia

1. Anaphylaxis is an acute reaction leading to severe physiologic derangements of multiple systems. True anaphylaxis denotes an IgE antibody–mediated reaction.

2. Non–IgE-mediated reactions resembling true anaphylaxis occur and are commonly called anaphylactoid reactions. These reactions can be of identical severity to anaphylactic reactions, may be clinically indistinguishable during the time of occurrence, and should be treated in an identical manner to anaphylactic reactions.

3. Clinical symptoms include urticaria, flushing, nausea, vomiting, abdominal pain, laryngeal edema, bronchospasm, and cardiovascular collapse. Under anesthesia, cardiovascular collapse and respiratory distress are the most common clinical signs.

4. Treatment consists of discontinuing the suspected initiating agent, securing the compromised airway, and establishing intravenous access. Bronchospasm and laryngeal edema are treated with epinephrine. Hypotension and cardiovascular collapse are treated with volume, epinephrine, and cardiopulmonary resuscitation if needed.

5. Evaluation of an anaphylactic reaction starts with a detailed history and may include skin testing, radioallergosorbent testing, and/or provocative challenge. Such efforts should be coordinated with the primary physician and an allergy specialist. The anesthesiologist's information about the timing and administration of the various medications and the signs and symptoms observed will be invaluable for the ultimate diagnosis of specific allergy.

6. Most serious and fatal allergic reactions to penicillin and β-lactam antibiotics occur in individuals who have never had a previous allergic reaction.

7. Many commonly used anesthetic agents and other drugs administered during anesthesia, including neuromuscular blocking agents, hypnotics, opiates, and antibiotics, lead to nonimmunologic histamine release.

8. True allergic reactions to local anesthetics are exceedingly rare, and cases labeled as such usually are due to other causes (vasovagal response, intravenous injection) or possibly metabolites (para-aminobenzoic acid), preservatives (methylparaben), or antioxidant additives (metabisulfite). If the previous drug is unknown, an amide-type local anesthetic should be chosen.

9. Diabetics exposed to protamine-containing insulin have a 40- to 50-fold increased risk for life-threatening reactions to protamine. Fish-allergic individuals and vasectomized men also may be at increased risk.

10. Health care workers regularly exposed to latex have a substantially increased risk of latex-specific IgE positivity (up to 18%), and 28% to 67% of children with spina bifida have a positive skin test result to latex proteins. Life-threatening anaphylaxis can occur intraoperatively in highly sensitive patients because of mucosal absorption of latex protein allergens from surgical gloves.

Anaphylaxis is an acute, severe, potentially life-threatening allergic reaction. The word "allergy," introduced by Baron Dr Clemens von Pirquet in 1906, was meant to describe the uncommitted biologic response that may lead to immunity or allergic disease. This concept is very much in keeping with our evolving understanding a century later. Preceding von Pirquet's neologism, Portier and Richet in 1902 reported that the second injection of sea anemone extract into dogs resulted in a fatal systemic reaction after the first injection had no directly observable effect, a finding totally unexpected at the time. Richet fashioned the word "anaphylaxis" by combining the Greek ana ("contrary to") and phylaxis ("protection") to describe an adverse reaction following repeated exposure to a foreign protein rather than the intended immunization, or prophylaxis.

This chapter takes the view of the anesthesiologist as perioperative specialist, focusing on the sequence of preoperative evaluation of the patient with a possible history of allergy, pathophysiologically based intra- and perioperative management, and as a consultant to the patient's further care by primary and specialist physicians.

Why are some of us destined for a life of allergy and others not? We now know that our immune systems can choose from 2 pathways to express reactions to antigens, either a low-grade or high-grade immunologic response (Table 86-1). Low-grade responders produce allergen-specific IgG1 and IgG4 antibodies and their T cells respond to the allergen with a moderate proliferation and production of interferon-γ by type 1 T-helper (Th1) cells. High-grade responders, however, have an exaggerated response, with increased production of allergen-specific IgE antibodies, as well as increased serum levels of IgE-specific antibodies to common allergens. In this group, cytokines produced by Th2 cells, including interleukin (IL)-4, IL-5, and IL-13, are produced rather than cytokines such as interferon-γ and IL-2 from Th1 cells.1

IgE-Mediated Mast Cell Activation

Antigenic molecules (usually proteins) capable of stimulating IgE antibody production may cause IgE-mediated anaphylaxis after initial sensitization and subsequent reexposure. Haptens, molecules too small to stimulate immune responses themselves, may bind to endogenous proteins such as albumin and become antigenic. Once produced, IgE antibodies to these antigens become fixed to tissue mast cells and/or circulating basophils, both of which contain high-affinity IgE receptors (Fig. 86-1).2,3 Reexposure to antigens or haptens, with subsequent cross-linking of cell surface IgE antibody, induces activation of membrane-associated enzymes, causing biochemical cascades that lead to an influx of extracellular calcium and mobilization of intracellular calcium with the subsequent release of preformed granule-associated mediators and generation of new mediators from cell membrane phospholipids.

Cytokines are low-molecular-weight chemicals that modulate cell function locally. The cytokines that promote IgE isotype switching (IL-4 and IL-13) are generated by T-lymphocytes with a Th2 cytokine profile. T cells that generate a Th1 cytokine profile—by secreting interferon-γ—inhibit B-cell isotype switching for IgE synthesis. Th1 and Th2 cells reciprocally inhibit each other's development. When IgE production is increased, such as in atopy (from the Greek atopos or "out of place"), an imbalance in the Th2/Th1 ratio control is likely. Th2-associated cytokines, such as IL-4, IL-5, IL-9, and IL-13, are associated with many stigmata of chronic allergic inflammation. IL-4 and IL-13 stimulate the production of IgE and vascular cell adhesion molecule (VCAM)-1. IL-5 and IL-9 are involved in the development of eosinophils. IL-4 and IL-9 promote the development of mast cells. IL-9 and IL-13 promote airway hyperresponsiveness. IL-4, IL-9, and IL-13 promote the overproduction of mucus. In their turn, eosinophils injure mucosal surfaces by releasing toxic basic proteins, cysteinyl leukotrienes, and platelet-activating factor. They also damage inhibitory MK2 muscarinic receptors, ultimately leading to airway hyperresponsiveness. IL-5 also releases mature and immature eosinophils from bone marrow.

IgE molecules then bind to high-affinity receptors for IgE (Fc epsilon receptor I [Fc∈RI]) on circulating basophils and mast cells. This binding itself does not induce the allergic reactions; a second step is required. The allergens, because of their multivalency, express multiple epitopes recognized by specific IgEs and IgGs. Simultaneous multivalent binding of allergens to several membrane-bound IgEs induces receptor aggregation, triggering a signaling cascade that leads to the production and release of allergic and inflammatory mediators (histamine, leukotrienes, chemokines, and cytokines).2 Release of these mediators is rapid (in minutes) and produces immediate symptoms.

There is a balance of activating and inhibitory cell-surface receptors, but how is the signaling cascade generated? Fc∈RI has an IgE-binding unit (the α-chain) and a signaling unit (1 β-chain and 2 γ-chains). Aggregation of Fc∈RI induces activation of a tyrosine kinase bound to the β-chain; the tyrosine kinase then phosphorylates 2 tyrosine residues in the γ-chains. These tyrosine residues are a central feature of the immunoreceptor tyrosine-based activation motif (ITAM), a feature of many receptors throughout the immune system. After phosphorylation, the ITAMs of the γ-chains activate spleen tyrosine kinase (SyK), which, through activation of downstream pathways, induces the release of allergic mediators.

Modulation of these Fc∈RI pathways occurs via inhibition mediated by the IgG receptor Fcg receptor IIb (FcgRIIb). Allergen-specific IgGs form complexes with allergens that can, in turn, form a bridge between Fc∈RI and FcgRIIb. This bridge induces the aggregation of activating Fc∈RI with inhibitory FcgRIIb, which inhibits the activation pathways activated by Fc∈RI. This delicate balance of IgG counteracting IgE is putatively the central mechanism behind successful allergen desensitization. In its inhibition of ITAM, FcgRIIb contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), a modified version of ITAM present in Fc∈RI.

Making use of this membrane architecture, a chimeric molecule designed to bind both FcgRIIb and a specific IgE bound to Fc∈RI has been shown to create a bridge and inhibit allergic reactions, including allergen-mediated activation of basophils and mast cells in vitro as well as in a mouse model.4 Such a strategy not only could provide prophylaxis for specific allergic reactions, but in addition could displace allergens already bound to IgE, in which case it would help terminate ongoing anaphylactic reactions following initial exposure.

Complement-Mediated Mast Cell Activation

Complement was first identified as a heat-labile "principle" in serum that "complemented" antibodies in the killing of bacteria. Complement consists of a series of plasma and cell membrane proteins that lyse susceptible targets, promote phagocytosis, and generate peptide mediators of the inflammatory response. These anaphylotoxins cause mast cell and basophil mediator release, directly increase vascular permeability, make smooth muscles contract, cause platelet activation, and stimulate macrophages to produce thromboxane, effects almost identical to IgE-mediated mast cell activation. The job of the complement system is challenging: it provides host defense through opsonization, chemotaxis and activation of leukocytes, and lysis of bacteria and cells. It also acts to augment the antibody response and enhance immunologic memory. Finally, it must dispose of waste through clearance of immune complexes from tissues and clearance of apoptotic cells.

The complement cascade may be activated through the classical, alternative, or the mannose-binding lectin pathway (Fig. 86-2).5 Complement activation through the classical pathway is initiated through IgG or IgM antibody binding to antigens, as in hemolytic ABO-incompatible blood transfusion reactions. Heparin–protamine complexes have been shown in vivo6 and in vitro7 to activate complement via the classical pathway. Injection of preformed immune complexes or IgG aggregates can activate complement and mimic clinical anaphylaxis. Patients with selective IgA antibody deficiency may develop IgG anti-IgA antibodies after receiving multiple transfusions, which may result in complement activation and anaphylactic reactions.8

Complement activation via the alternative pathway may be stimulated by lipopolysaccharides (endotoxin),9 althesin,10 radiocontrast media, and membranes used for cardiopulmonary bypass and dialysis.

The initiators of the mannose-binding lectin pathway are microbes with terminal mannose groups. Young children with recurrent infections may have low levels of mannose-binding lectin, suggesting the importance of the mannose-binding lectin pathway in the loss of passively acquired maternal antibody and the acquisition of a mature immunologic repertoire.5

The 3 pathways converge at the point of cleavage of C3, leading to formation of the membrane attack complex that directly affects the integrity of mast cell and basophile cell membranes. In addition, complement activation has an adjunctive role in amplifying the antibody response.

Nonimmunologic Mast Cell Activation

Certain drugs can cause mast cell mediator release by nonimmunologic means, the exact mechanism of which is poorly understood but may be differentiated from immunologically mediated mast cell activation in certain ways. Nonimmunologic stimulation relies heavily on cellular Ca++, is unaffected by neuraminidase treatment, shows rapid inactivation, and elicits no increase in the incorporation of 3H-methyl groups into the lipid fraction. In contrast, stimulation by immunologic agents relies primarily on extracellular Ca++, is inhibited by neuraminidase treatment, shows a comparatively slow rate of inactivation, and causes a significant increase in the incorporation of 3H-methyl groups into the lipid fraction. The clinical implication of differentiating the 2 mechanisms is that prophylactic intervention may be affected; experimentally, pretreatment of mast cells with neurotensin desensitizes them to subsequent stimulation by compound 48/80.11 Moreover, there are different mast cell phenotypes (eg, connective tissue mast cells, airway mast cells) that may vary in expression following activation.12 Drugs that induce nonimmunologic mast cell activation include opiates, especially morphine and codeine,13,14 and neuromuscular blocking agents such as atracurium and D-tubocurarine.12 Intriguingly, there seems to be a disparity between a higher incidence of reaction to rocuronium in Europe and in the United States.15

Mediators of Anaphylaxis

Once the mast cell, basophil, or eosinophil is activated by any of the mechanisms, release of mediators results in the attraction, accumulation, and activation of other cellular elements. Mediators released include those preformed and stored in granules and those newly generated upon appropriate stimulation. Release of these mediators causes various pathophysiologic responses that result in acute or chronic reactions. The complex of allergen, IgE, and high-affinity receptor for IgE on the surface of the mast cell triggers noncytotoxic, energy-dependent release of preformed, granule-associated histamine and tryptase, and the membrane-derived lipid mediators leukotrienes, prostaglandins, and platelet-activating factor. Mast cells produce the 3 cysteinyl leukotrienes C4, D4, and E4, which cause contraction of smooth muscles, vasodilatation, increased vascular permeability, and hypersecretion of mucus. Collateral sources of cysteinyl leukotrienes are eosinophils, macrophages, and monocytes. Mast cell tryptase activates receptors on endothelial and epithelial cells, which causes the upregulation of adhesion molecules that selectively attract eosinophils and basophils.

Allergic disease is on the increase in Western countries. Environment may have a great deal to do with this increase; allergic disease was less common in East Germany than West Germany prior to reunification.16 This finding supports the so-called "hygiene hypothesis," the notion that when the developing immune system is deprived of microbial antigens that stimulate Th1 cells, the opportunity to prolong sensitization of Th2 cells ensues. By promoting a Th1 response, infection downregulates the tendency for development of Th2-related disease.17,18 Other factors that may favor a greater Th2 response in infants include diet, birth dates during high pollen counts, viral infections, allergen exposure, tobacco smoke, and air pollutants.

The incidence of anaphylaxis during anesthesia is variable within an order of magnitude, but ranges between 0.5:10000 and 16.3:10000 in adults19-23 and 5:10000 in children.24 Anaphylaxis during anesthesia has been attributed primarily to muscle relaxants, although there is an intriguing geographical variability. For example, muscle relaxants are the most commonly reported allergenic agents in France (∼50%) with latex (∼20%) and antibiotics (∼15%) following.25 A review of 826 patients referred to an anesthetic allergy clinic in Australia over a 17-year period revealed severe immediate anaphylactic reactions in 54%; in 59% a muscle relaxant was involved.20 In a single center in Norway, muscle relaxants were the most common cause (93.2%) of IgE-mediated reactions, with latex approximately 3.6%. In 2 Spanish centers, antibiotics were the main etiology (44% of the 56% of patients with confirmed IgE-mediated reactions), and muscle relaxants were determined to be the cause in 37% and latex in 4%.26 Local/cultural patterns of sensitization as well as underlying genetic factors likely play an important role in these variations. Gender differences are often found in allergic reactions; rodent studies have confirmed an estrogen effect on mast cell activation and allergic sensitization, and progesterone is shown to suppress histamine release but potentiate IgE induction.27

Patients who react have a greater incidence of allergy, atopy, asthma, and previous reactions than do nonreactors, suggesting that these are significant comorbidities. However, although a history of drug allergy was found in 37% of cases and atopy in 38%,28 most patients do not have such a history, and most patients with such a history do not react.29 In patients with suspected or unexplained hypersensitivity reactions during anesthesia, follow-up evaluation strongly suggests anaphylaxis as a possible etiology, with an increase in estimated incidence from 2.1:10000 to 3.1:10000,30 underscoring the importance of allergy evaluation following such an event. A multicenter survey carried out in France in 1990 and 1991 revealed a 3:1 ratio of females to males in a series of 1585 patients. The reactions occurred mostly in adults (80%); 9% occurred in children.23 Cardiovascular collapse has consistently been described as the most common presenting problem, and evidence indicates that this form of shock is substantially different at the cellular level and potentially more harmful than other causes of shock.31

The evaluation and treatment of patients who develop anaphylaxis in the operating room is challenging even for the experienced clinician. In the perioperative period, multiple medications are frequently given in close proximity, making causative factors more difficult to interpret. Patients usually are unconscious, draped, and cold—situations that often hide early signs and symptoms of anaphylaxis. Anesthetics themselves alter mediator release, possibly delaying early recognition.32

In general, symptoms begin soon (within minutes) after introduction of the causative agent, but may be delayed for 1 to 2 hours. Along with other symptoms, conscious patients frequently describe a sense of impending doom. The primary anaphylactic target organs in humans are the cutaneous, gastrointestinal, respiratory, and cardiovascular systems (Box 86-1). During general and regional anesthesia or during deep sedation, cardiovascular signs predominate.20,33 The speed and scope of initial intervention should be guided by the speed and severity of the reaction, which can be graded in a standard fashion (Table 86-2).

In a conscious patient, anaphylaxis is most easily confused with a vasovagal reaction, which may occur when a patient collapses after an injection or painful procedure (Box 86-2). However, respiratory distress does not occur, and symptoms are relieved almost immediately once the patient is supine. Vasovagal reactions are often also accompanied by profuse diaphoresis and bradycardia, without flushing, urticaria, angioedema, prorates, or wheezing. The differential diagnosis of sudden collapse includes dysrhythmias, myocardial infarction, aspiration of food or foreign body, pulmonary embolism, seizure disorder, hypoglycemia, and stroke. In the presence of laryngeal edema, especially when accompanied by abdominal pain, the diagnosis of hereditary angioedema should be considered. Globes hysterics and factitious asthma must be considered when respiratory symptoms are present. Other conditions that can mimic anaphylaxis are overdose of medication, cold urticaria (especially if generalized), idiopathic urticaria, carcinoid tumors, and systemic mastocytosis.

See references 34-38

Anaphylactic reactions must be recognized and treated early because death may occur within minutes. Treatment of anaphylactic reactions can be divided into initial and secondary therapies (Box 86-3).

Initial Treatment

When possible, steps should be taken to interrupt further exposure to and absorption of the offending agent. Intravenous infusions of suspected allergens should be stopped immediately. Airway maintenance with 100% oxygen should be administered; continuous monitoring via pulse oximetry and arterial blood gas levels should ensure adequate oxygenation. If there is any suggestion of airway compromise due to laryngeal edema, the trachea should be intubated immediately. If laryngeal edema is present, aerosolized epinephrine (3 inhalations of 0.16- to 0.20-mg epinephrine per inhalation from a metered dose inhaler) or epinephrine by nebulizer (8-15 drops of 2.25% epinephrine in 2 mL normal saline) may be useful. If laryngeal edema is refractory to these measures or progresses too rapidly, a needle catheter cricothyrotomy, emergency surgical cricothyrotomy, or tracheostomy may be necessary.

Upon suspicion of a severe reaction, intravenous access should be established (if not already present), and intravascular volume should be maintained with administration of isotonic crystalloid (normal saline) or colloidal solutions. Potent volatile anesthetic agents should be discontinued in order to minimize negative inotropic effects, decreases in systemic vascular resistance, and interference with the reflex compensatory response to hypotension. Halothane specifically sensitizes the heart to circulating catecholamines, which are required for treatment of severe anaphylactic reactions; therefore, change of agents to an ether anesthetic such as isoflurane, sevoflurane, or desflurane is recommended if continued inhalation anesthesia is required.

Epinephrine is the cornerstone of initial pharmacologic treatment. In adults with severe hypotension or airway obstruction, 100-μg increments (typically 0.1 mL of a 1:1000 dilution) of epinephrine should be given intravenously, usually not exceeding 0.5 mg total, but dosage may be varied depending on severity, response, and patient factors (age, weight, etc). Risks of epinephrine include cardiac dysrhythmias (particularly if halothane is used), myocardial infarction, and stroke. In the rare instance when an intravenous access is not present, 300 μg of epinephrine can be given subcutaneously or intramuscularly, or 1 mg (10 mL of 1:10000 epinephrine) can be administered through the endotracheal tube. However, when a patient is in shock, the absorption of intramuscular or subcutaneous epinephrine is unreliable. For persistent hypotension, catecholamine infusions can be used. Epinephrine also will be useful if hypotension and bronchospasm persist. Suggested starting doses of epinephrine are given in Box 86-3, based on recommendations made by the Australian Patient Safety Foundation from their review of allergic adverse events during the Australian Incident Monitoring Study (AIMS).39 The timing of epinephrine therapy also contributes significantly to effective treatment. In a review of fatal anaphylaxis, Pumphrey determined that epinephrine was used in the treatment of 62% of fatal anaphylactic reactions, but before arrest in only 14%. Ironically juxtaposed, adrenaline overdose caused at least 3 deaths in this review40 and has been the subject of warning in a case report of treatment of nonanaphylactic allergic reactions.41

If more than 8 to 10 μg/min of epinephrine is required, tachycardia may be a significant side effect and norepinephrine may be more effective. The suggested starting dose for norepinephrine is 0.05 μg/kg/min (2-4 μg/min in adults) and should be titrated to maintain tissue perfusion. Dopamine can also be used to maintain blood pressure and perfusion. A dose of 5 to 20 μg/kg/min may help maintain cardiac output, thereby improving coronary, cerebral, renal, and mesenteric blood flow. There is an emerging role for vasopressin as an adjunct to (but not a replacement for) epinephrine. In a rat model as well as case reports of refractory anaphylactic shock, there is evidence for improved survival with epinephrine-vasopressin combination therapy over epinephrine alone.42,43

Secondary Treatment

Once the patient's condition begins to stabilize, administration of additional drugs may be warranted. An antihistamine such as diphenhydramine will be helpful for symptomatic relief of itching. Although no evidence has demonstrated the effectiveness of H2-receptor antagonists in the treatment of anaphylaxis, ranitidine (1 mg/kg intravenously [IV]) may be useful44 when hypotension is persistent because the effects of histamine on endothelial H2 receptors may exacerbate peripheral vasodilatation.

Glucocorticoids are useful for preventing potential late-phase reactions and treating persistent bronchospasm. Traditional teaching suggested that steroids provided no immediate effect, but there is an emerging understanding that membrane transactivation pathways are more rapid than previously recognized and therapeutic effects of steroid administration can occur within minutes.45 Hydrocortisone 5 mg/kg (up to 200 mg initial dose) and then 2.5 mg/kg every 6 hours or methylprednisolone 1 mg/kg initially and every 6 hours may be given as indicated. Treatment with bicarbonate is controversial and probably should be reserved for profound acidosis, preexisting hyperkalemia, or use immediately after intubation following prolonged cardiac arrest. Acid-base status must be monitored using arterial blood gas levels to guide further therapeutic interventions.

The response to therapy usually is prompt, but despite all of the measures mentioned previously, some patients do not respond quickly, particularly in the form of shock known as refractory anaphylactic shock, for which evidence is emerging that arginine vasopressin in combination with epinephrine and intravascular volume administration is more effective in rat models and humans than epinephrine or vasopressin alone.42,43 The treatment of anaphylaxis may be complicated by the use of β-adrenergic blocking agents, particularly in older patients. Beta-blocker therapy is associated with an increase in the severity and, possibly, the incidence of acute anaphylaxis during acute antigen exposure, as well as during immunotherapy. Anaphylaxis under these conditions may be severe, protracted, and resistant to conventional treatment because of the β-adrenergic blockade.46,47

Role of Test Doses and Pretreatment to Prevent Anaphylaxis

Many clinicians choose to routinely administer a small amount of drug ("test dose"), such as an antibiotic, prior to administering the balance of the calculated dose. For IgE-mediated reactions, the test dose may or may not cause anaphylaxis; the lack of an immediate response does not guarantee absence of anaphylaxis with subsequent dosing,48 but probably is a reflection of the antigen load, the IgE phenotype of the patient, and the elapsed time since the previous reaction.

Pretreatment regimens are particularly effective when used for repeat exposure to radiocontrast media in patients with previous reactions; these are discussed below. Desensitization as a form of pretreatment can be used for patients who must be reexposed to a medication known to have caused a previous reaction; however, the clinician must evaluate the risks, benefits, and alternatives to the readministration of the specific medication. This situation is discussed below as well.

Patients who have had anaphylactic reactions require proper evaluation to identify the causal agents and to guide the selection and use of future medications; without rigorous investigation, some patients will be labeled with an incorrect allergy and some will be put at risk for subsequent reexposure to a real allergen.49 The evaluation starts with a detailed history, including concurrent illness and earlier allergic and anesthetic encounters—it is here where the anesthesiologist can shine as a perioperative expert. It is helpful to prepare a flow diagram of the patient's reaction, temporally depicting the clinical manifestations of the reaction and the medications received, including indications, when initiated, doses, and duration of therapy. Equally important information includes previous exposure to the same or structurally related medications, effect of drug discontinuation, response to treatment, and any previous diagnostic testing or rechallenge. Medications should be considered with regard to their known propensity for causing anaphylaxis. The proximity of drug administration to the onset of acute reactions should be documented. In general, agents that have been used for long, continuous periods before the onset of an acute reaction are less likely to be implicated than are agents recently introduced or reintroduced. However, in the perioperative period, patients commonly receive many medications in close temporal proximity, making a diagnosis by history alone difficult.

Immunodiagnostic Tests

Skin Testing for Immediate Hypersensitivity Reactions

Skin testing is commonly used by allergists in the diagnosis of immediate hypersensitivity to aeroallergens and Hymenoptera, but the evaluation of drug allergy is hampered by the unavailability of relevant drug metabolites or appropriate multivalent testing reagents. Yet intradermal skin tests are still the most readily available and generally useful diagnostic tests for drug allergy. Skin testing clearly has an established role in the evaluation of IgE-mediated penicillin allergy.34 Skin testing also is useful in the evaluation of allergy to muscle relaxants,35,36 barbiturates,35,37 chymopapain,38 streptokinase,39 insulin,40 latex,41,42 and miscellaneous drugs. Specific protocols for skin testing are well documented. Skin testing must be performed in the absence of medications that will affect the skin test response (especially H1 antihistamines, tricyclic antidepressants, and sympathomimetic agents). Appropriate positive (histamine) and negative (diluent) controls should be used. Anesthesiologists should seek consultation with allergists for such evaluations; they should avoid informal and uncontrolled allergy evaluations using dilute intradermal solutions or patch tests performed without proper controls.

Other In Vivo Tests

Delayed (tuberculin-like) skin tests have little, if any, place in the evaluation of drug allergy. Patch tests may be of value in cases of contact dermatitis.

In Vitro Tests

Total Serum IgE Levels

Although increases in total serum IgE levels have been reported after allergic reactions,43 the level of antigen-specific IgE is rarely, if ever, helpful in establishing the diagnosis of an allergic drug reaction.

Assays to Measure Complement Activation

Assessment of complement activation includes measurement of the decrease in complement components (C4, C3, or total hemolytic complement [CH50]) and increase in the generation of products of complement activation (C3a, C4a, C5a, and so on). If positive, these assays may implicate complement activation in specific reactions.

Release of Histamine and Other Mediators

Washed leukocytes containing basophils with IgE antibody on their cell surfaces release histamine and other mediators when incubated with relevant antigens. Although this in vitro basophil–histamine release assay avoids drug exposure to the patient, the assay is clinically impractical because it requires whole blood drawn immediately before the test; presently the test is limited to research laboratories.

During or shortly after allergic reactions, blood can be obtained and analyzed for the release of various mediators. Urine also can be analyzed for metabolites of histamine or prostaglandin D2 (PGD2). Plasma histamine and PGD2 levels remain increased only briefly, limiting their clinical use. Measurement of serum tryptase, a protease released specifically from mast cells, is useful for the assessment of mast cell–mediated allergic reactions.25,33,37,50 Two forms of tryptase have been identified; b-tryptases appear to be the main isoenzymes expressed in mast cells and are a marker for mast cell mass, whereas in basophils, a-tryptases predominate and tend to be more of a marker for systemic mastocytosis. Serum tryptase (total tryptase, the sum of a and b) may remain elevated for hours after mast cell activation due to anaphylaxis. With nonallergenic histamine release, although histamine levels are elevated, tryptase typically remains normal.

Radioallergosorbent Testing

The radioallergosorbent test (RAST) was first introduced in 1967. It measures circulating allergen-specific IgE antibody. The basic principle of the RAST is simple: the allergen is attached to a solid-phase (carbohydrate particle, paper disk, or wall of polystyrene test tubes or plastic microtiter wells) and incubated with the serum under study, during which time a specific antibody of all immunoglobulin classes is bound. The particles are washed, and a second incubation is undertaken with a radiolabeled, highly specific anti-IgE antibody. After washes, the bound radioactivity is directly related to the allergen-specific IgE antibody content in the original serum. When performed appropriately, the RAST correlates well with skin test end point titration, basophil–histamine release, and provocation tests. Results from the serum under study are compared with a positive reference serum and a negative control serum. False-positive tests may occur because of high nonspecific binding, high total serum IgE levels, or poor technique. False-negative tests may occur because of interference of high levels of IgG "blocking antibodies" or inability to maximize assay sensitivity.

If a patient has experienced an allergic reaction to a medication in the past but must receive that medication again, the physician must evaluate the risks and benefits of readministration of the medication in question. If equally effective and non–cross-reacting alternative drugs are available, they should be used. If alternative drugs fail, induce unacceptable side effects, or are clearly less effective, then cautious administration of the drug using a premedication regimen or a desensitization protocol (prescribed by an expert allergist) may be considered. Premedication regimens (Box 86-4) have been tested, validated, and used most often in patients with previous reactions to radiocontrast media (RCM) who again require readministration of radiocontrast.51-53

Specific immunotherapy, consisting of the administration of increasing concentrations of allergen, has 3 mechanisms of action: downregulation of the cytokines produced by Th2 cells, upregulation of the cytokines produced by Th1 cells, and upregulation of regulatory T cells. As a result, allergic inflammation is inhibited, cytokines that control the production of IgE (interferon-γ and IL-12) are increased, IgG-blocking antibodies are enhanced, and cytokines involved in allergen-specific hyporesponsiveness (IL-10 and transforming growth factor-β) are increased. Specific immunotherapy is not without its risks, with anaphylaxis being the most prominent because of the relative crudeness of the allergen extracts. As recombinant technology becomes more available and precise, hypoallergenic isoforms of immunotherapy may minimize the risk of anaphylaxis. Additional strategies include naturally occurring hypoallergenic isoforms, DNA vaccines, blockade of IgE or its synthesis, and interruption of the Th2-dependent allergic cascade. In addition, several ways of specifically inhibiting IL-4 and IL-5 currently are being investigated.17 This basic understanding informs our targeting of new approaches to treatment.

Neuromuscular Blocking Drugs

Muscle relaxants are a common cause of anaphylactic reactions during anesthesia, with IgE-mediated mechanisms including positive Prausnitz-Kustner tests, basophil–histamine release studies, inhibition of basophil–histamine release after desensitization to anti-IgE, and demonstration of drug-specific IgE antibodies are observed in sera from patients with adverse reactions to muscle relaxants.20,54-58

Extensive in vitro cross-reactivity has been reported between muscle relaxants and other compounds that contain quaternary and tertiary ammonium ions.59-61 Insofar as these compounds are found in many drugs, foods, cosmetics, disinfectants, and industrial materials, patients may become sensitized through environmental contact. Sensitization to ammonium ion epitopes in cosmetics has been postulated to explain the predominance of reactions in women.61 Although the exact incidence of allergic reactions caused by muscle relaxants is unknown, reactions to muscle relaxants are less common in the United States than in France and Australia.

Hypnotics

Acute allergic reactions have been reported after administration of thiobarbiturates, especially thiopental. Proposed mechanisms for thiobarbiturate reactions include nonimmunologically induced mediator release and IgE-mediated reactions. A thiopental RAST has been developed,62 and mast cell histamine release to thiopental in vitro has been described.63,64

Anaphylaxis to propofol with laboratory confirmation has been reported in only 2 patients,65,66 without laboratory confirmation (therefore a presumptive diagnosis) in an infant with egg and peanut allergy,67 and in 2 adult patients, one of whom had a pruritic maculopapular rash around the eyes (for 3 months)68 and one of whom died from cardiovascular collapse with increased serum tryptase and methylhistamine levels at postmortem.69 Although warnings about administration of propofol to patients with egg allergy can be strident, the lecithin in the propofol emulsion containing ethylenediaminetetraacetic acid (EDTA) as a preservative is derived from egg yolk, not egg albumin found in egg white. In most patients with egg allergies, egg albumin is the sensitizing protein. In the propofol emulsion using metabisulfite as the preservative, metabisulfite may be the allergenic component. Because the propofol emulsion also contains soybean oil, patients with soybean oil allergy should not receive propofol.

Local Anesthetics

Despite patients commonly reporting "allergic reactions" to local anesthetics, true allergic reactions to injected local anesthetics are exceedingly rare. Adverse reactions to local anesthetics often are the result of vasovagal reactions, toxic reactions (probably caused by accidental intravenous injection), side effects from epinephrine, or psychomotor responses such as hyperventilation. Toxic symptoms often involve the central nervous and cardiovascular systems and may produce slurred speech, euphoria, dizziness, excitement, nausea, emesis, disorientation, or convulsions. Vasovagal reactions are usually associated with bradycardia, sweating, pallor, and rapid improvement in symptoms when the patient is supine. Sympathetic stimulation, either from epinephrine or anxiety, may result in tremors, diaphoresis, tachycardia, and hypertension. Rarely, signs of reactions to local anesthetics are consistent with IgE-mediated mechanisms such as urticaria, bronchospasm, and anaphylactic shock.70 IgE-mediated sensitivity has, on rare occasions, been reported to parabens, preservatives used in local anesthetics.

Local anesthetics are divided into 2 general chemical classes, the esters and the amide compounds (Box 86-5). Ester local anesthetics are metabolized to para-aminobenzoic acid (PABA); therefore, ester local anesthetics cross-react and patients may present with allergic or hypersensitivity reactions. In addition, individuals allergic to other drugs metabolized to PABA, such as sunscreens and methylparaben preservatives, may experience a cross-reaction. There is no cross-reaction with the amide compounds. Epinephrine-containing local anesthetics with the antioxidant metabisulfite may be allergenic because of the metabisulfite component.71,72

Evaluation of the patient with a history of adverse reactions to local anesthetics should include a complete history of the episode, skin testing, and incremental drug challenge. The local anesthetic tested should be appropriate for the proposed procedure and not expected to cross-react with the drug implicated in the previous reaction. If the previous drug is unknown, an amide-type local anesthetic should be chosen. In a patient with a history suggestive of an IgE-mediated reaction or possible paraben sensitivity, preparations without paraben should be used for testing, challenge, and treatment. Preparations with epinephrine should not be used for skin testing because they may mask a positive skin test and induce toxic effects.

Narcotics

Narcotics typically cause nonimmunologically mediated histamine release from skin mast cells rather than anaphylaxis. In vitro studies suggest that skin mast cells are uniquely sensitive to narcotics, whereas gastrointestinal and lung mast cells and circulating basophils do not release histamine when exposed to narcotics.13,14,73 Most opiate-induced reactions are self-limited, cutaneous, and restricted to hives and pruritus or mild hypotension treated by fluid administration. This nonimmunologic release of mediators is a far more common clinical occurrence than are the rare reactions induced by morphine-specific IgE antibody.

Antibiotics

See references 74 and 75.

Penicillin Antibiotics

Outside of the operating room, but also within our sphere of responsibility during resuscitation or perioperative care, penicillin antibiotics are the most common medications causing allergic drug reactions (0.7%-8% of treatment cases).76,77 From 0.004% to 0.015% of penicillin treatment courses end in anaphylaxis, resulting in 400 to 800 deaths per year in the United States. Only 10% to 20% of patients who claim an allergy to penicillin react to skin testing with the major and minor determinants.

A low-molecular-weight chemical, penicillin must covalently combine with tissue macromolecules to produce multivalent hapten–protein complexes. The β-lactam ring, which opens spontaneously under physiologic conditions, forms the penicilloyl group. Other metabolic pathways result in additional antigenic determinants, known as the "minor determinants." Anaphylactic reactions to penicillin usually are mediated by IgE antibodies directed against minor determinants, although some anaphylactic reactions have occurred in patients with only penicilloyl-specific IgE antibodies.

Individuals with a history of penicillin reactions have a 4- to 6-fold increased risk for subsequent reactions to penicillin compared to those without previous reactions.78 However, most serious and fatal allergic reactions to penicillin and β-lactam antibiotics occur in individuals who have never had a previous allergic reaction. Sensitization of these individuals may have occurred from their last therapeutic course of penicillin or (less likely) by occult environmental exposures. Approximately 10% to 20% of hospitalized patients claim a history of penicillin allergy; however, many of these patients either have been incorrectly labeled as allergic to penicillin or have lost their sensitivity. The most useful single piece of information in assessing an individual's potential for an immediate IgE-mediated reaction is the skin test response to major and minor penicillin determinants.

Negative skin tests indicate that penicillin antibiotics can be given safely. A limited number of patients with positive skin tests have been treated with therapeutic doses of penicillin. The risk of an anaphylactic or accelerated allergic reaction ranges from 50% to 70% in such patients.79 Therefore, if skin tests are positive, equally effective non–cross-reacting antibiotics should be substituted when available. If alternative drugs fail, induce unacceptable side effects, or clearly are less effective, then administration of penicillin using a desensitization protocol to reduce the risk of anaphylaxis should be considered.

Cephalosporins

Like penicillins, cephalosporins possess a β-lactam ring (Box 86-6), and allergic reactions were reported shortly after cephalosporins came into clinical use. Cross-reactivity between penicillins and cephalosporins is about 10% because of this common β-lactam ring structure,80 and standard teaching was to avoid treatment with cephalosporins for those with possible penicillin anaphylaxis. However, evidence has accumulated that the side chain rather than the β-lactam ring is the antigen in cephalosporin allergic reactions. Because first-generation cephalosporins as well as cefamandole have similarities in their side chains, in general, patients with positive skin tests to any penicillin reagent or a history compatible with immediate hypersensitivity should not receive first-generation cephalosporin antibiotics unless alternative drugs are clearly less desirable.37 For the most part, later-generation cephalosporins have significantly greater gram-negative antimicrobial properties, with decreased activity against gram-positive organisms. The fourth-generation cephalosporins have broad-spectrum activity.

The carbapenems and monobactams (aztreonam) are 2 additional classes of β-lactam antibiotics. Cross-reactivity between penicillin and carbapenems would be expected on the basis of the structure of the drugs. There are no published data on allergy to meropenem in patients who are allergic to carbapenem or penicillins. Allergic reactions to the monobactam aztreonam are thought to involve the side chain, so cross-reactivity with other β-lactams should be rare.

Vancomycin

Although anaphylaxis to vancomycin is rare, hypotension is a serious immediate adverse effect associated with intravenous administration. Direct myocardial depression81 and nonimmunologically mediated histamine release82 have been reported as mechanisms of vancomycin-induced hypotension, and not IgE-mediated anaphylaxis. The hypotension occurs most commonly when the drug is rapidly infused or is administered in a concentrated solution. Vancomycin-associated hypotension may be exacerbated by the concurrent use of other drugs (eg, anesthetics) that cause vasodilatation and/or have a negative inotropic effect.81 In addition to hypotension, vancomycin can produce the "red neck" or "red man" syndrome, an intense erythematous discoloration of the upper trunk, arms, and neck that may be associated with pruritus in conscious patients. Vancomycin also has been associated with the sudden development of throbbing pain or spasm in the chest or parasternal muscles in conscious patients, without evidence of myocardial ischemia. To minimize the risk of reactions, vancomycin should be infused over a period of at least 60 minutes and in a dilute solution (500 mg/100 mL). Reactions should be treated by discontinuation of the infusion, administration of an antihistamine for pruritus, and the use of vasopressors and other interventions (eg, fluids) that counteract the hypotension.

Sulfonamides and Trimethoprim

Sulfonamides are generally safe and are often used for chronic prophylaxis. Occasionally, they cause allergic reactions such as minor skin rashes after approximately 1 week of therapy. Life-threatening reactions have been described in HIV-infected infants reexposed to sulfamethoxazole-trimethoprim (SMX-TMP). Stevens-Johnson syndrome and toxic epidermal necrolysis have been associated with SMX-TMP treatment, presumably mediated by an immune reaction similar to graft versus host disease.83 Despite concerns having been raised about other sulfonamide-containing drugs such as diuretics, sulfonylureas, and celecoxib, these antimicrobial agents have an aromatic amine group and a substituted ring not found in the nonantibiotic sulfonamide-containing drugs, so cross-reactivity seems unlikely.84,85

Other Classes of Antibiotics

Development of a serious allergic reaction to non–β-lactam antibiotics, such as the aminoglycosides, is rare. Nonurticarial rashes can be treated with antihistamines.

Multiple Antibiotic Allergy Syndrome

The multiple antibiotic allergy syndrome, wherein certain individuals are recognized as making "generic" allergic antibody to unrelated antibiotics, is an evolving entity.86 Female gender, a history of multiple antibiotic reactions, and reactions to nonsteroidal anti-inflammatory drugs appear to be the main risk factors.87

Radiocontrast Media

Adverse, allergic-type reactions induced by radiocontrast media (RCM) injections may occur immediately or have a delayed presentation. Most immediate reactions, the event for which an anesthesiologist would likely be summoned, begin 1 to 3 minutes after intravascular administration. Fatal reactions after radiocontrast administration result in an estimated 500 deaths annually in the United States. Patients with a previous reaction to RCM have an approximately 33% (range 17%-60%) chance of a repeat reaction on reexposure.52 Depending on the chemistry of the RCM (Table 86-3), if ionic RCM was administered previously, the use of nonionic RCM will result in a 10-fold decrease in a severe immediate repeat reaction.88

The exact mechanism of adverse reactions to RCM is unknown. Intravascular injection activates complement, either by the classic or the alternative pathway89; therefore, production of anaphylatoxins with subsequent mast cell and basophil mediator release has been suggested as the cause of these reactions. However, RCM are capable of inducing nonimmunologic histamine release from mast cells and basophils in the absence of complement activation; hypertonicity has been suggested as the cause, as has an IgE-mediated cause based on elevated tryptase levels, particularly with severe or fatal reactions.90-93

Pretreatment of high-risk patients with oral prednisone (50 mg) and diphenhydramine (50 mg) 1 hour before radiocontrast administration reduces the risk of reactions to 9% (Box 86-4).94 Almost all reactions in pretreated patients are of no clinical importance (eg, mild urticaria). The addition of oral ephedrine (25 mg) 1 hour before radiocontrast administration (in patients without angina, dysrhythmias, or other contraindications for ephedrine administration) further reduces the reaction rate to 3.1%.53 Combining premedication with nonhyperosmolar contrast media may be of additional benefit in preventing reactions in high-risk individuals.51

Protamine

Protamine sulfate, a polycationic protein extracted from salmon milt, is used to reverse heparin anticoagulation and slow the absorption of certain insulins (Neutral Protamine Hagedorn, or NPH, and protamine zinc insulin, or PZI). The use of intravenous protamine following cardiopulmonary bypass, cardiac catheterization, hemodialysis, or pheresis has resulted in increasing reports of life-threatening adverse reactions.

Diabetic patients receiving daily subcutaneous injections of insulins containing protamine have a greatly increased risk for life-threatening reactions when given protamine intravenously.95-97 Another group that may be at increased risk for protamine reactions are men who have undergone vasectomies. After vasectomy, 55% to 73% of men will develop antibodies to sperm antigens, and of this group, 20% to 33% develop autoantibodies to protamine.98 In addition, because protamine is produced from the matured testis of salmon or related species of fish belonging to the family Salmonidae or Clupeidae, it has been suggested that individuals allergic to fish may have serum antibodies directed against protamine.99 Finally, prior exposure to intravenous protamine given for the reversal of heparin anticoagulation may increase the risk for a reaction with subsequent protamine administration.100,101 Following cardiopulmonary bypass, risk factors found to correlate with adverse events following protamine administration included NPH insulin use (odds ratio = 8.18; 95% confidence interval [CI] 2.08-32.2), fish allergy (odds ratio = 24.5; CI 1.24-482.3), and a history of nonprotamine medication allergy (odds ratio = 2.97; CI 1.25-7.07).91

The exact mechanisms by which acute protamine reactions occur are incompletely understood. Some protamine reactions may be associated with complement activation, either through protamine–heparin complexes or through the interaction of protamine and complement fixing, antiprotamine IgG antibody, leading to pulmonary artery pressure elevation through the generation of thromboxane.102,103

Topical Preparations

Cutaneous hypersensitivity and eczema may occur from chronic exposure to topical preparations. Of 50 case reports of chlorhexidine anaphylaxis, one-third occurred during surgery104; however, the risk of development of type I and type IV allergy to chlorhexidine, even with daily occupational exposure of health care workers, is extremely rare.104 The intriguing explanation for allergic reactions lies in the fact that its molecular structure is symmetrical, with 2 identical epitopes. Therefore, it is capable of cross-linking mast and basophil cell surface IgE antibodies, thereby promoting degranulation and allergic reactions in sensitized individuals. This mechanism is similar to other divalent drugs such as succinylcholine. Moreover, sensitization to chlorhexidine is likely because of its presence in numerous consumer products such as cleaning fluids, toothpastes, mouth rinses, etc.

Concerns are often expressed about allergy to iodine in the context of povidone iodine preparation solutions or in patients with a history of seafood allergy. Similar concerns are voiced about patients with allergy to RCM because of the iodine component. The reaction to povidone iodine is typically allergic contact dermatitis or local irritation. There is, however, 1 case report of anaphylaxis to povidone-iodine applied intravaginally, but because of the lack of follow-up allergy testing, it is unclear if this reaction was caused by the iodine or the povidone.105 Povidone is the carrier molecule for iodine atoms. A 9-year-old child has been confirmed to have eosinophilia, elevated specific IgE level, and a positive skin prick test for povidone iodine.106 Fish allergy is due to protein M and tropomyosin, neither of which contain iodine.107,108

Transfusion-Related Anaphylaxis

Transfusion-related anaphylaxis, a serious, life-threatening condition, is discussed in Chapter 83.

Natural Rubber Latex

Natural rubber latex present in various materials, especially surgical gloves, is responsible for a dramatic change in the etiology of intraoperative anaphylactic shock, increasing in 1 series from 0.5% of cases in 1989 to 22.3% in 2002.

Natural rubber latex is a complex suspension of polyisoprene, lipids, phospholipids, and proteins. The proteins are found in 3 physical states: water soluble, starch bound, or latex bound, and there are at least 240 potentially allergenic proteins in the processed latex product. The protein content of latex gloves can vary up to 1000-fold among different lots marketed by the same manufacturer and 3000-fold between gloves from different manufacturers.109 A number of chemicals, including preservatives, accelerators, antioxidants, and vulcanizing compounds, are added during the manufacturing process to yield the final product. Although the chemicals added to latex have long been associated with contact dermatitis and type IV reactions, it was only after the embracing of universal precautions that reports from around the world describing generalized urticaria, angioedema, upper and lower respiratory obstructions, and cardiovascular collapse first appeared. Patients who have suffered severe systemic reactions often have a history of contact urticaria or angioedema to rubber products such as gloves or rubber balloons, or atopy.

Certain populations are at significantly increased risk for latex allergy. These include health care workers, who have had increased exposure to latex usually in the form of gloves; patients with prolonged or frequent exposure to latex products such as urinary catheters; and latex factory workers.110 A health care worker who is atopic is at increased risk, and the risk is increased if he or she had prior surgery.111 Anesthesiologists have a 12.5% and 2.4% prevalence of latex sensitization and allergy, respectively.112 Patients with meningomyelocele or congenital urologic anomalies seem particularly susceptible, with an estimated incidence of latex allergy averaging 50%.

IgE antibodies play a major role in the immunopathogenesis of latex-induced allergy and anaphylaxis. The diagnosis of latex allergy is made by a combination of medical history, physical examination, and reliable in vivo or in vitro tests. Although skin prick testing is both sensitive (100%) and specific (99%), this method should be restricted to patients with a compelling history and an inconclusive serologic test result because of possible systemic reactions. The RAST for latex-specific IgE is recommended, although it is less sensitive than skin prick testing.

Serum tryptase levels in the immediate postanaphylaxis period may be helpful in confirming the diagnosis following a clinical episode. The positive predictive value of tryptase for the diagnosis of anaphylaxis is 92.6%, and the negative predictive value is 54.3%.113 Multiple allergies are often found in latex allergic patients. Cross-reactivity of latex with tropical fruits is not uncommon,114 and such findings in the history can be used to heighten suspicion about a patient's potential for latex allergy.

Patients who have had serious allergic reactions to latex and patients at high risk (eg, patients with meningomyelocele) should avoid contact with latex products. Because prophylactic drug protocols have proven ineffective, a latex-safe environment is advocated.115,116 Box 86-7 provides a checklist for dealing with the latex-allergic patient. Moreover, patients in high-risk pediatric groups, such as children with urologic birth defects and myelomeningocele, should be offered latex-free exposure in the operating room from birth to avoid subsequent sensitization. The American Society of Anesthesiologists has a brochure available on its website summarizing current recommendations for anesthesiologists caring for latex-allergic patients.117

1. Once an allergen is identified, the most important clinical strategy is avoidance of that allergen. As perioperative specialists, anesthesiologists have a critical role in understanding the etiology, treatment, and evaluation of patients' allergic reactions.

2. Epinephrine is the most important medication to have available and to provide in the setting of anaphylaxis. Early administration of the appropriate dose is crucial for optimum outcome because the outcome of shock due to anaphylaxis may be far worse than other forms of shock. For prophylaxis or attenuation of an anticipated allergic response, effective protocols exist that reduce the risk of anaphylaxis to less than 0.5%. Following primary treatment, adjunctive, or secondary, treatment (antihistamines, anticholinergics, β- and α-agonists) is important for patient comfort and reduction of symptoms of anaphylaxis.

3. Specific immunotherapy strategies are emerging for a variety of allergens to which patients and health care workers have become exposed. Chronic as well as acute desensitization strategies exist that reorganize an individual's profile from primarily a Th2 to a Th1 type of response. Because of the increasing understanding of the immune response, strategies now can be developed for therapeutically interfering with the interaction of IgE and allergen, inhibiting cytokine function and T-cell activation, or modifying allergy cell responsiveness.

4. There is an important epidemiologic challenge in explicating the reasons for the increasing incidence of allergic disease, particularly in Western countries.

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