Risk Factors

There are many factors that increase the risk of anaphylaxis in the population. Patients with atopy are at a higher risk of anaphylaxis from antigens administered by the mucosal route, such as food, compared with parenterally administered agents, such as vaccines. The longer the interval between doses for certain antigens, the less likely is a recurrence of anaphylaxis. Interruption of therapy may lead to predisposition to anaphylactic reactions, as has been documented with insulin treatment. Route of administration appears to be a risk factor, with a higher likelihood of anaphylaxis when an agent is given by injection rather than orally. Gender and age have been evaluated as potential risk factors. Women have a higher incidence of anaphylaxis in general compared to men and also have anaphylaxis more often in reaction to latex, muscle relaxants, and aspirin. Men have a higher rate of anaphylaxis in reaction to insects than do females. These higher rates based on gender may be more related to exposure than to a genetic difference. Adults tend to have a higher incidence of anaphylaxis to contrast medium, insects, plasma expanders,

Table 2

Etiological and Pathophysiological Classification of Anaphylaxis and Anaphylactoid Reactions

Anaphylaxis-IgE-mediated reactions Drugs Food

Insect bites and stings Allergen immunotherapy Latex

Exercise (some cases) Anaphylactoid

Disturbances in arachidonic acid metabolism Aspirin

Nonsteroidal anti-inflammatory drugs Immune aggregates y-globulin IgG-anti-IgA

Possibly protamine, dextran, and albumin Director release of mediators from mast cells and basophils Drugs Idiopathic Exercise

Physical factors (cold or sunlight) Miscellaneous and multimediator activity

Nonantigen- antibody-mediated complement activation Radiocontrast material Possibly some cases of protamine reactions Dialysis membranes and anesthetics than children do. Again, this may be more a result of greater exposure to these agents in adults than children.

The route of administration of a particular agent can exert an effect on both the frequency of occurrence and the severity. Anaphylaxis can occur with any route, including oral, subcutaneous, intramuscular, intravenous, intranasal, intraocular, Cutaneous, intravaginal, intrarectal, and intratracheal. Attacks seem to be more severe and more frequent when the route of administration is injection.

ETIOLOGY

Although any substance has the potential to cause anaphylaxis, the most common causes of IgE-mediated anaphylaxis are medications, foods, insect bites and stings, latex, and allergen immunotherapy injections. Table 2 lists the etiological and pathophysiological classifications of anaphylaxis and anaphylactoid reactions. The following discussion is a review of some of the more common substances known to produce anaphylaxis.

Medications

Hundreds of agents have been documented as causes of anaphylaxis, and medications comprise one of the largest groups (Table 3). Penicillin and its derivatives are one of the

Table 3

Medicinal Agents Causing Anaphylaxis

Antibiotics

Chemotherapeutic agents Miscellaneous

Penicillin and derivatives Asparaginase

Cephalosporins

Tetracycline

Sulfonamides

Ciprofloxacin

Nitrofurantion

Vancomycin

Vincristine

Cyclosporine

Methotrexate

5-fluorouracil

Radiocontrast material

Heparin

Vaccines, (tetanus, measles, influenza, mumps) Dextran Protamine Local anesthetics Glucocorticosteroids Antithymocyte globulin

Aspirin

NSAIDs inflammatory Opiates

Human gamma globulin Insulin

NSAIDs, nonsteroidal anti-inflammatory drugs.

most common causes of anaphylaxis to medication. Penicillin has been reported to cause fatal anaphylaxis at the rate of 0.002% in the general population, or 1 fatality per 7.5 million injections. Estimates of nonfatal anaphylaxis vary, ranging from 0.7 to 10%. Cross-reactivity exists between the various penicillins. All p-lactam antibiotics (penicillins, cephalosporins, monobactams, carbapenems, oxacephems, clavams, carbacephems) contain the main four-member p -lactam ring linked to a second five- or six-member ring, except for the monobactams, which lack the second ring. A list of p-lactam antibiotics can be seen in Table 4. There is much cross-reactivity with ampicillin, but only minimal cross-reactivity with methicillin and oxacillin. Cephalosporins also cross-react with penicillin in up to 30% of patients with allergy. Aztreonam, a p-lactam with a monobactam structure, can be used safely in patients with penicillin allergy. Anaphylaxis can occur from parenteral, oral, or topical drug administration, although the highest incidence is from parenteral administration.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are important causes of anaphylactoid events. These reactions are not IgE-mediated. They apparently produce anaphylactoid reactions through the aberrant mechanism of arachidonic acid, with inhibition of cyclooxygenase and subsequent increased production of leukotrienes. However, some episodes may be caused by the direct degranulation of mast cells. Adverse reactions to aspirin typically include urticaria, angioedema, asthma, chronic rhinosinusitis, and nasal polyps in sensitive individuals. Because the sensitivity persists for life, management entails strict avoidance. Acetaminophen is the alternative recommended drug. Studies have suggested that the cyclooxygenase-2 inhibitors are safe in aspirin-sensitive asthmatics, but they do not have Food and Drug Administration (FDA) approval at this time. Salsalate, choline salicylate, magnesium salicylate, and propoxyphene hydrochlo-ride are the other drugs that can be used.

All NSAIDs may cross-react with aspirin to varying degrees. Desensitization can be considered in aspirin-sensitive patients with respiratory disease.

Table 4 ß-Lactam Antibiotics

Penicillins Penicillin G Penicillin V Methicillin Oxacillin Carbenicillin Ticarcillin Mezlocillin Piperacillin Cloxacillin Nafcillin Ampicillin

Clavams

Clavulanic Acid

Monobactams Azteonam

Carbapenems Imipenem Meropenem Carbacephems Loracarbef

Cephalosporins Cephalothin Cefazolin Cephalexin Cefadroxil Cephalothin Cefamandole Cefuroxime Cefonicid Cefpodoxime proxetil Cefaclor Cephalexin

Cefotetan Cefotaxime Cefitozime Ceftriaxone

Cefoperazone Ceftazidime Cefixime Cefprozil

Oxaceophems Moxolactam

Foods

Any food has the potential to cause anaphylaxis, but some foods are more allergenic than others. The most frequent causes of food anaphylaxis include peanuts, tree nuts, crustaceans, fish, eggs, and dairy products.

Table 5 gives a representative listing of foods reported to cause anaphylaxis. The incidence of anaphylactic reactions to foods is unknown, but may be more common than stinging insect anaphylaxis. A review of patients with a history of food-related anaphylaxis who had been instructed in epinephrine self-administration demonstrated that these patients required injections at a rate of 0.97 times a year, which was three times higher than that required in insect-allergic individuals. It appears that certain foods cause anaphylaxis more frequently in children than in adults and vice versa. The most common offender in adults is probably shellfish, whereas in children they are milk, eggs, and peanuts.

The peanut is responsible for allergic reactions in both children and adults. Over the last several decades the incidence of peanut allergy in children has dramatically increased. Now, about 1% of children in the United States have peanut allergy. Peanut allergy is probably the most common cause of death from food anaphylaxis in the United States. Peanut allergy, unlike other food allergies, is rarely outgrown, with only about

Table 5 Foods Causing Anaphylaxis

Legumes (peanuts, beans, peas, soybeans)

Shellfish (shrimp, lobster, crab, crawfish)

Milk

Eggs

Wheat

Fish

Nuts (cashews, almonds, pecans, walnuts)

Seeds (sesame, sunflower, poppy, cottonseed)

Spices (cinnamon, nutmeg, mustard, sage)

Fruits (apples, bananas, peaches, oranges, melons)

Chocolate

Potato

Corn

20% of patients losing their sensitivity over time. Once a diagnosis has been made, peanuts should be treated with strict avoidance. Patients with peanut allergy should be warned of "hidden" peanuts in many foods, including candy, chili, spaghetti sauce, and egg rolls.

If it is not apparent from the patient's history what food triggered the anaphylaxis, then skin testing with different food extracts may help in isolation of the cause. Although rare, it is important to note that prick skin testing with foods can itself cause an anaphylactic reaction. Therefore, using an in vitro test such as the radioallergosorbent assay (RAST) test, although less sensitive in determining the allergen, may be safer for verifying a particular food as the etiological agent when the history suggested a severe anaphylactic reaction to that food.

Insect Bites and Stings

Anaphylaxis occurs from stings of Hymenoptera insects, including bees (honeybee, bumblebee, and sweat bee), vespids (wasps, yellow jackets, and hornets), and imported fire ants. The importance of each of these insects as causes of anaphylaxis varies according to the geographic region. Bee and yellow jacket stings cause the most problems in the northern portions of the United States, with wasps and fire ants causing most problems along the Gulf Coast. As compared with Hymenoptera stings, anaphylaxis from insect bites is rare. Bites from kissing bugs and deerflies have been documented to cause IgE-mediated anaphylaxis.

Adults who have only skin manifestations of anaphylaxis or any other organ system involvement warrant skin testing with insect venoms. In contrast, it is recommended to skin test children for insect venoms only if they have skin manifestations along with involvement of one other organ system. Studies suggest that children with only skin reactions such as urticaria and angioedema after venom sting do not worsen on repeated stings and lose their sensitivity over time. If positive, appropriate venom immunotherapy should be instituted. In addition to venom immunotherapy, the individual should carry an autoinjector of epinephrine, wear a medical identification bracelet, and practice insect-avoidance procedures.

Latex

The incidence of latex allergy has increased dramatically in the past 10- 15 yr with the increased use of latex gloves in response to the universal precautions associated with AIDS and other infections. Latex is now a significant cause of anaphylaxis, with more than 1000 cases of latex anaphylaxis reported to the Food and Drug Administration between 1988 and 1992. Three groups appear to be at high risk for development of anaphylaxis to latex: health care workers, people with a history of pruritus from exposure to latex objects, and patients with spina bifida.

Many different latex proteins have been demonstrated to be allergenic. Some allergens have been isolated from natural latex, and others are produced from the processing of the rubber compound. Exposure to latex can be topical, inhalational, mucosal (from surgical and dental procedures), and intravenous. Patients with latex allergy also have a high incidence of anaphylaxis to certain foods, including bananas, kiwi fruit, chestnuts, and avocados. They should therefore be counseled regarding these foods.

Allergen Immunotherapy

Allergen immunotherapy is an important modality in the treatment of select patients with allergic rhinitis, asthma, and insect venom hypersensitivity. By giving increasing doses subcutaneously of the allergen(s) the patient is sensitive, increased tolerance to these allergens occurs. Unfortunately, immunotherapy has been associated with very low rates of anaphylaxis. Bernstein et al. in 2004 reported that fatal reactions to immunotherapy occurred every 1 per 2.5 million injections, with an average of 3.4 deaths per year in the United States. A number of risk factors are associated with such severe anaphylac-tic reactions to immunotherapy, including errors in dosage, failure to reduce the dosage after a longer than scheduled interval, administration of the wrong extract, inadvertent intravenous administration, failure to postpone injection because of asthma exacerbation, failure to observe patients for an appropriate length of time, and concurrent use of p -adrenergic blocking agents. All allergen immunotherapy should be given in a medical care setting and patients observed for at least 20 min after the injection for the possibility of anaphylaxis. No injections should be given if the patient is having asthma symptoms or is on p-adrenergic blocking agents.

Exercise-Induced Anaphylaxis

Exercise has been documented as a source of severe anaphylactoid reactions. Symptoms include angioedema, urticaria, abdominal cramping, diarrhea, laryngeal edema, bronchospasm, and respiratory distress. The reaction typically begins during exercise or shortly after exercise is completed. A special group of patients with exercise-induced anaphylaxis have symptoms only when they exercise within 2- 4 h of eating. This entity is called food-dependent exercise-induced anaphylaxis. Some patients with this condition have symptoms with exercise only after eating certain foods, such as celery, wheat, shellfish, and oysters. Others have symptoms in association with any food and exercise. All individuals with these conditions should exercise with a companion capable of administering epinephrine. Individuals with food-dependent exercise-induced ana-phylaxis should not exercise within 2-4 h of eating. About two-thirds of individuals with exercise-induced anaphylaxis have a family history of atopy, and about one-half have a personal history of atopy. The exact mechanism is unknown, and it has been speculated that the release of endogenous opioid peptides with vigorous exercise may release mediators in susceptible individuals. There is also evidence for mast cell activation in skin biopsy from patients with exercise-induced anaphylaxis.

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