Recognizing and treating an anaphylactic reaction are only part of managing this life-threatening condition. Equally important is preventing a recurrence by finding out what caused the episode.
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Recognizing and treating an anaphylactic reaction are onlypart of managing this life-threatening condition. Equally important is preventinga recurrence by finding out what caused the episode.
Anaphylaxis in an adolescent or child is a medical emergency. Clinically,it is a dramatic presentation of the classic signs and symptoms of TypeI hypersensitivity1--an immediate systemic reaction to rapid, IgEmediatedrelease of potent mediators from tissue mast cells and peripheral bloodbasophils. An anaphylactoid reaction, though clinically indistinguishablefrom anaphylaxis, is believed not to be IgE mediated but probably involvesmany of the same mediators, such as histamine. These mediators cause cutaneous,respiratory, cardiovascular, and gastrointestinal signs and symptoms, singlyor in combination. In a biphasic anaphylactic reaction, early signs andsymptoms resolve, only to recur several hours later.2 The box ("Histamineand the inflammatory cascade") describes the pathophysiology of anaphylaxis.
In addition to knowing how to manage an anaphylactic reaction, pediatriciansmust be able to determine the cause of the episode, so the allergen canbe avoided in the future. They also should know how to distinguish anaphylaxisfrom other conditions with which it can be confused.
The prevalence of anaphylaxis is unknown since it is not subject to reportingrequirements. In addition, numerous cases probably are misdiagnosed, andmany patients simply avoid what they know has caused a mild anaphylacticreaction and don't consult a physician. Data extrapolated from a Danishstudy suggest that the United States probably has about 8,300 cases of anaphylaxiseach year, resulting in approximately 415 deaths.6 Drugs, foods,and insect stings accounted for virtually all of the anaphylactic reactionsin the study.
Food was the most common cause of anaphylactic reactions outside thehospital in a retrospective survey of cases of anaphylaxis treated in theMayo Clinic Emergency Department, accounting for more cases than bee stingand drugs combined. Peanuts and tree nuts were the foods that most oftencaused serious anaphylactic reactions.7 A five-year, unpublished surveyof anaphylactic reactions treated at the Children's Hospital of Philadelphiaalso showed that food allergy was the most common cause of anaphylaxis outsideof the hospital.
Investigators have studied the relationship of many other factors toincidence of anaphylaxis, including age, gender, route of administrationof the inciting agent, and atopy.
The hallmark of an anaphylactic reaction is the onset of symptoms withinseconds to minutes after exposure to the allergen. At least some symptomsalmost always are apparent during the first hour. Generally, the later theanaphylactic signs and symptoms begin, the less severe the reaction. About25% to 30% of patients experience a biphasic reaction; in the first phase,the patient typically develops classic symptoms, then appears to be recoveringand may even become asymptomatic. Significant, often catastrophic, symptomsthen recur in the second phase.13 Most reports suggest that theearlier epinephrine, the drug of choice for anaphylaxis, is administeredthe better the prognosis, but early treatment does not necessarily affectthe prevalence of biphasic or protracted symptoms, which may last from oneday to three weeks.13
Clinical signs and symptoms of anaphylaxis vary in onset, severity, responseto therapy, and course and can affect one or more systems (Tables 1 and2). In a review of 266 cases of anaphylaxis in adults and children, skinwas the organ most often affected; 90% of the subjects had hives or angioderma,while others were flushed or itchy but had no rash.14 The upper and lowerairways were also problem areas, with 60% of patients having shortness ofbreath, dyspnea, and wheezing. Dysphagia, dysphonia, choking, tongue swelling,and laryngeal edema were noted in 24% of subjects. The cardiovascular systemalso was often affected, with almost half of patients clinically symptomatic(dizziness, lightheadedness, or tachycardia) or having documented hypotension.Gastrointestinal symptoms were common; 46% had nausea, vomiting, cramping,and diarrhea. Sometimes individuals with anaphylaxis report a feeling of"impending doom." Up to 30% of individuals with exercise-inducedreactions have headaches, but this is otherwise an uncommon symptom. Othercommon signs and symptoms in anaphylaxis include periocular and nasal pruritus,sneezing, profuse perspiration, disorientation, fecal or urinary urgencyor incontinence, and uterine cramping. In some instances, the initial manifestationof anaphylaxis is loss of consciousness. Death may follow an anaphylacticattack within minutes, or days to weeks. Late deaths are generally causedby organ damage early in the course of anaphylaxis.
Several factors appear to increase the risk of having an anaphylacticreaction that is severe (Table 3). Patients taking b-adrenergic antagonistsor calcium-channel blockers may be resistant to standard therapeutic regimensand therefore at increased risk for severe anaphylaxis.15 Reports on fataland near-fatal anaphylactic reactions to foods suggest that children withasthma are at increased risk for severe symptoms.13 Patients with insectsting allergy and those whose anaphylaxis was triggered by immunotherapymay develop significant, acute bronchospasm along with other symptoms ofanaphylaxis, studies show.16,17 Anaphylaxis should never be ruled out becausethe child does not have skin symptoms.
Because the onset of anaphylaxis is abrupt and dramatic, the diagnosisgenerally is readily apparent. The initial step in determining the causeof an episode is a careful history. When symptoms begin soon after the childhas eaten a particular food, the cause of the anaphylactic episode may beeasy to determine. In addition to foods, the most common culprits in childrenand adolescents are drugs, insect stings, and latex. Vaccines occasionallyare responsible. Exercise-induced anaphylaxis, food-related exercise-inducedanaphylaxis, and idiopathic anaphylaxis are less common in children thanin adults.
Foods. Several factors appear to predispose an individual to food-inducedanaphylaxis or affect its severity, including a personal or family historyof atopy, age, and dietary exposure to the inciting food. Atopic patientswho also have asthma are at greater risk of developing severe food-allergicreactions than atopic patients without asthma.13,18
Individuals inherit the ability to produce antigen-specific IgE to foodproteins, though it has not been conclusively shown that hypersensitivityto a specific food is inherited. Theoretically, exposure and sensitizationto food allergens must precede the initial anaphylactic reaction. Reportsof an anaphylactic reaction after the first known exposure to a food substanceare numerous, however. In a recent study of patients with either peanutor tree nut allergy, almost 75% of the patients who were allergic to peanutshad a clinical reaction on their first known exposure.19
Several possibilities may explain this apparent paradox. The most likelyis that the infant was sensitized to foods passed in breast milk. Anotherpossibility is that the infant had the antigen without the parents' knowledge--ina milk formula consumed in the newborn nursery, in food given by a substitutecaregiver, or in a food product that was not suspected of containing theantigen in question. Sensitization also may occur because of cross-sensitizationto a similar allergen; for example, a latex-sensitive individual may beallergic to kiwi or banana. Sensitization also may occur in utero.20
Any food may precipitate an anaphylactic reaction, but those most oftenimplicated are peanuts, tree nuts, fish, and shellfish. Individuals typicallydo not "outgrow" sensitivities to these foods, in contrast tomilk, eggs, and soybeans. The incidence of food allergy appears greatestin the first two years of life and decreases with age. Consequently, foodsintroduced during the first year, such as cow's milk, egg, soy, wheat, andpeanut (as peanut butter) are more apt to induce hypersensitization.11
Onset of milk allergy is usually in the first year of life, with about85% of infants "outgrowing" their sensitivity by the third yearof life.21 The first symptoms of milk allergy are often in the oropharynxand may include edema and pruritus of the lips, oral mucosa, palate, andpharynx. Young children may scratch at their tongue, palate, the front ofthe neck, or the external auditory canals.
Food allergy can develop at any age, though it appears most often inthe first three years of life. It is not uncommon for an individual to havea major allergic reaction in middle age to a food she has eaten her entirelife. While the episode may be a complete surprise, detailed questioningmay reveal that the food in question produced some minor symptoms, suchas oral pruritus or nausea and cramping, on an earlier occasion. Cookingor processing of some foods may remove, diminish, or even enhance theirallergenicity.
To determine if a particular food has caused a major allergic reaction,ask about the type and quantity of food the child ate and when she ate it,how much time elapsed before the symptoms developed, whether the food wascooked or raw, other times when she had similar symptoms and if she atethe food on those occasions, and whether there appear to be any other precipitatingfactors, such as exercise. When it is not obvious what food has caused areaction, take a dietary history that reviews all ingredients of the suspectmeal, including any concealed ingredients or food additives. Peanuts orpeanut butter, for example, is frequently added to cookies, candies, pastries,or chili, spaghetti, and barbecue sauces. Table 4 lists foods that mostoften cause anaphylaxis.
Incidence of food-dependent exercise-induced anaphylaxis appears to beon the rise, possibly because of the increased popularity of exercisingduring the past decade. Two forms of this type of anaphylaxis have beendescribed: reactions following the ingestion of specific foods (such ascelery, shellfish, or wheat) and reactions following the ingestion of anyfood, though this is rare.22 In both forms, anaphylaxis occurs when a patientexercises within two to four hours of ingesting the implicated food; whenthe patient does not exercise after eating the food, she has no ill effects.23This disorder is twice as common in females as males, and more than 60%of those who have it are younger than 30. The initial symptom is generalizedpruritus, which progresses to urticaria and erythema, respiratory obstruction,and cardiovascular collapse. Patients with specific food-dependent exercise-inducedanaphylaxis generally have positive prick skin tests to the food that provokessymptoms and a few are known to have reacted to the food when they wereyounger.
The laboratory evaluation of patients with an anaphylactic reaction tofood should be directed at identifying specific IgE antibodies to the foodin question. IgE antibody can be recognized in vivo by prick or punctureskin testing. A negative prick/puncture skin test is an excellent predictorof a negative IgEmediated food reaction to the suspected food. A positiveprick skin test does not necessarily mean that the food is the incitingagent, but if the patient also has a classic history of anaphylaxis to thatfood, the positive test is a good predictor of allergic reactivity. Patientswith an unequivocal history of anaphylaxis following the isolated ingestionof a food to which they have evidence of significant IgE antibodies shouldnot take part in double-blind placebo-controlled food challenges; challengeis not necessary for diagnosis and may be life threatening. If the patientingested several foods and has positive skin tests to them, however, itis essential to identify the responsible food, using a carefully controlledfood challenge.
The possible limitations to skin testing need to be recognized. Someobservers speculate that skin testing shortly after anaphylaxis may failto yield a positive response because of temporary anergy (diminished reactivityto specific antigens). Other causes of false-negative prick skin tests includeimproper technique, concomitant use of antihistamines, and the use of foodextracts with reduced or inadequate allergenic potential.
Medications. Allergic drug reactions account for 10% to 25% of all adversedrug reactions.24 Most of these reactions are mild, but the potential foranaphylaxis makes it essential to identify the offending drug so it canbe avoided. Parenteral administration poses the highest risk of drug-relatedanaphylaxis, though it can occur with any route. Penicillin and its derivativesare among the most common offenders, with cross reactivity reported acrossthe group. There has been one fatality per 7.5 million penicillin injections,with estimates of nonfatal anaphylaxis ranging from 0.7% to 10%.1,25 Adversereactions to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) havebeen recognized for years. The spectrum of clinical reactivity may reflectboth IgE and nonIgE mediated mechanisms. Aspirin sensitivity is associatedwith two types of clinical presentation: chronic rhinitis, sinusitis, nasalpolyps, and asthma; or chronic urticaria with or without angioedema. Crossreactivity between aspirin and NSAIDs has been reported in 99% of NSAIDchallenges.26
Drug allergy may be difficult to diagnose, particularly in the patienton multiple medications. Although skin testing or in vitro testing witha limited number of drugs, such as penicillins and cephalosporins, helpsconfirm the allergy, such testing is not usually available, so the onlydefinitive testing is by oral challenge. The risks in such a procedure maybe great, and challenge is therefore contraindicated in patients in whomthe antigen has been defined. Challenges should be performed by trainedpersonnel with immediate access to emergency equipment, preferably in anintensive care setting.
Insect stings. Stinging insects, which are in the Hymenoptera order,include apids (honeybees, bumblebees, and sweatbees), vespids (yellow jackets,hornets, and wasps), and formicids (ants). The incidence of Hymenopterasting allergy in children is 0.4%, and in the US about 40 children die eachyear from insect stings.24 Imported fire ants are increasingly causing anaphylaxis,particularly in the southern and western US. Children are likely to be exposedto these insects.
In diagnosing insect sting allergy it is important to differentiate systemicreactions with the classic signs of anaphylaxis from large local reactionsand toxic reactions. In a large local reaction, signs and symptoms, includingswelling, occur around the sting site. Toxic reactions, which develop aftermultiple stings, may mimic anaphylaxis, but are mediated by vasoactive chemicalsin the venom itself rather than by IgE. Toxic reactions caused by multiplestings generally do not require further investigation. Anaphylaxis aftera single sting merits evaluation by venom skin testing to determine whatinsect is the culprit and the individual's sensitivity. Diagnostic studiesare not indicated for large local reactions because these reactions do notappear to predispose to systemic reactions.
Children with systemic skin symptoms have a 5% to 10% risk of systemicreactions with future envenomation.24 Thus, testing and immunotherapy generallyare not recommended for these patients. Children who have any other systemicsymptoms should be tested for venom-specific IgE antibodies, however. Skintesting is the preferred method because it is more sensitive than immunoassays.Venom immunotherapy is indicated for children who have extracutaneous systemicreactions to insect stings and positive skin test responses to one or morevenoms. At a maintenance dose of 100 mg the clinical efficacy of vespidvenom is 98%; it is slightly less for honeybee.24 In addition to receivingimmunotherapy, the child should carry epinephrine, wear a medical ID, andavoid insects.
Latex. Anaphylaxis to latex is becoming more of a concern as the useof latex gloves increases. During a recent four-year period, more than 1,000cases were reported to the Food and Drug Administration.27 Among children,patients with spina bifida and genitourinary abnormalities, and those requiringmultiple surgical procedures are at greatest risk. Any medical, surgical,or dental procedures on patients with spina bifida or a history of latexallergy should be performed in a latex-controlled environment. That is,no latex gloves are used in the room, and no latex accessories come in contactwith the patient.
Children at high risk for latex allergy and those whose clinical historysuggests allergy should undergo skin testing for latex hypersensitivity.An extract for this purpose is available in many allergy centers. In vitroassays for IgE to latex are also useful, but generally are less sensitive.The individual with systemic sensitivity to latex should avoid contact withlatex, wear a medical alert tag, and have epinephrine available.
Some conditions may be confused with anaphylaxis. Scombroid poisoning(from fish), factitious allergic emergency, and vasovagal collapse are examples.In the absence of urticaria and angioedema, one must consider arrhythmia,myocardial infarction, hereditary angioedema, aspiration of a bolus of food,pulmonary embolism, and seizure disorders.
When laryngeal edema is present, especially accompanied by abdominalpain, hereditary angioedema is a possibility. This disorder usually beginsless abruptly than anaphylaxis and does not include urticaria, and it oftenis associated with a family history of similar reactions.
Systemic mastocytosis results in flushing, tachycardia, pruritus, headache,abdominal pain, diarrhea, and syncope.
A so-called factitious allergic emergency may result when patients deliberatelyand secretly ingest a substance to which they are known to be allergic,resulting in anaphylaxis.
Vasovagal syncope after an injection or a painful or disturbing situationmay cause the patient to collapse. The child or adolescent typically lookspale and complains of nausea before the syncopal episode, but does not feelitchy or become cyanotic. The child has no problem breathing, and symptomsresolve almost immediately after he lies down. Profuse diaphoresis, slowpulse, and maintenance of blood pressure generally are part of the syndrome.
Hyperventilation may cause breathlessness and collapse. It is usuallynot associated with other signs and symptoms of anaphylaxis, except fortingling in the hands and around the mouth. Blood pressure and pulse aregenerally normal.
Vocal cord dysfunction is another disorder that may mimic the respiratorysymptoms of anaphylaxis. The diagnosis, which is suggested by the absenceof other manifestations of anaphylaxis, may be confirmed by laryngoscopywith paradoxical adduction of the vocal cords.
In many patients with anaphylaxis, limited prick skin testing is necessaryto confirm the cause of the anaphylactic reaction. In cases where the limitedtesting does not reveal the cause, more extensive prick testing may be helpful.The clinician must decide how many skin tests are practical and justified,by weighing the anticipated low yield of positive results in idiopathicanaphylaxis against the value of discovering a cause of this serious disorder.
When extreme hypersensitivity seems likely, alternative approaches maybe warranted, including the use of an in vitro test, such as the radioallergosorbenttest (RAST). Overall, the RAST is considered less sensitive and specificthan the prick skin test
Massive activation of mast cells during anaphylaxis results in a dramaticrise in plasma histamine and, somewhat later, a rise in plasma or serumtryptase. Plasma histamine rises during the first several minutes of a reactionand generally stays up briefly; measurement is impractical because it requiresspecial collection and handling techniques. Whether measurement of urinarymethylhistamine is useful in documenting anaphylaxis remains to be demonstrated.
Serum tryptase rises over the first hour and may remain elevated formany hours. It is fairly stable at room temperature and can be obtainedfrom postmortem specimens. Tryptase can be an important serological markerwhen the diagnosis of anaphylaxis is unclear.
Physicians spend hours preparing to manage an acute attack of anaphylaxis.Yet long-term management has the most impact on quality of life.
Acute management. An anaphylactic reaction can be fatal if not treatedimmediately.8,13 The longer therapy is delayed, the greater the incidenceof complications and fatalities, according to data on fatal bee stinginducedanaphylactic reactions.19 Before beginning treatment, rapidly assess theextent and severity of the reaction; the adequacy of oxygenation, cardiacoutput, and tissue perfusion; any potential confounding medications (suchas b-blockers); and what may have caused the reaction. Direct initial therapyat maintaining an effective airway and circulatory system.
The first step is to inject intramuscularly or subcutaneously 0.01 mL/kgof aqueous epinephrine 1:1,000 (maximum dose 0.3 to 0.5 mL, or 0.3 to 0.5mg). A second dose of epinephrine may be appropriate if the patient remainssymptomatic or unstable even after other supportive pharmacologic measures,discussed below, have been instituted. Intravenous administration of epinephrinemay cause fatal arrhythmias or myocardial infarction, particularly in adults,and should be reserved for refractory hypotension requiring cardiopulmonaryresuscitation. In patients with pulmonary symptoms, administer supplementaloxygen.
Outcomes in fatal and near fatal food-induced anaphylaxis show the importanceof epinephrine. In general, patients who die from an anaphylactic reactionhave received no epinephrine or an inadequate dose during their acute reaction.13,18In contrast, patients who have survived a near-fatal anaphylactic reactiongenerally receive epinephrine early and many have received repeated doses.On a few occasions, patients who received a single injection of epinephrinedied soon thereafter. Even with appropriate treatment in a medical facility,reversing an anaphylactic reaction sometimes is impossible.
To ensure that patients at risk for anaphylaxis receive epinephrine asearly as possible, instruct them, their family members, and other care providersabout how to administer it. Give a prescription for a preloaded syringewith epinephrine to patients who have had an anaphylactic reaction and tothose with asthma and food allergy, especially if to peanuts, nuts, fish,or shellfish. Premeasured doses of epinephrine can be obtained in two forms.The Epi-Pen delivers only a single dose, so two Epi-Pens may be prescribedfor patients who have experienced a previous anaphylactic reaction or whoare at high risk and do not have ready access to a medical center. The Ana-Guardand Ana-Kit each contain a special calibrated syringe that allows separatedelivery of two doses of medication. Instruct patients to administer thesecond dose if symptoms are getting worse or no response is seen withinfive to 10 minutes of the initial dose. The patient or family members shouldpractice with appropriate training devices to ensure that they know howto use whatever device they have. Epi-Pen trainers are available from themanufacturer to assist with instruction. Patients also must be aware thatpreloaded syringes have a one-year shelf life and need to be replaced eachyear. Sustained-release preparations of epinephrine are not appropriatefor acute anaphylaxis.
Once epinephrine has been administered, other therapies may be of benefit.Studies suggest that the combination of an H1 antihistamine (diphenhydramine--1mg/kg up to 75 mg) either intramuscularly or intravenously and an H2antihistamine (cimetidine--4 mg/kg up to 300 mg) administered intravenouslymay be more effective than either antihistamine administered alone. Intravenousadministration of the histamine antagonists should be slow because rapidinfusion is associated with arrhythmias (diphenhydramine) and with fallsin blood pressure (cimetidine). The role of corticosteroids in the treatmentof anaphylaxis remains unclear. Most authorities recommend giving prednisone(1 mg/kg orally) for mild to moderate episodes of anaphylaxis and methylprednisolonesodium succinate (Solu-medrol;
1 to 2 mg/kg intravenously) for severe anaphylaxis to modulate the late-phaseresponse. Patients who have been receiving glucocorticosteroid therapy shouldbe assumed to have hypothalamic-pituitary-adrenal-axis suppression and receivestress doses of hydrocortisone intravenously during resuscitation. If wheezingis prominent, we recommend administering an aerosolized b-adrenergic agent(albuterol), intermittently or continuously depending on the patient's symptomsand the availability of cardiac monitoring.
Aerosolized epinephrine may be useful for preventing life-threateningupper airway edema. Hypotension, due to a shift in fluid from the intravascularto extravascular space, may be severe and refractory to epinephrine andantihistamines. Depending on the patient's blood pressure, large volumesof rapidly infused crystalloid (lactated Ringer's solution or normal saline)are frequently required to reverse hypotension. Patients taking b-blockersmay require five to seven liters of fluid before pressure is stabilized.
Although epinephrine and fluids are the mainstay of treatment for hypotension,other vasopressor drugs may be necessary. Dopamine administered at a rateof 2 to 20 mg/kg/min while blood pressure is monitored can be lifesaving.In refractory cases or patients taking b-blockers, 1 to 5 mg of glucagongiven as a bolus followed by an infusion of 5 to 15 mg/min titrated againstclinical response may be helpful.
The best treatment of patients who have an anaphylactic attack whiletaking b-adrenergic blocking drugs remains a matter of some concern. Inchildren who do not respond to epinephrine because of b-blockade, glucagon1 mg given intravenously as a bolus may be beneficial. Administer a continuousinfusion of 1 to 5 mg glucagon per hour if needed. If combined b1and b2 receptors blockers such as propranolol are used, it maybe possible to administer epinephrine for its a-adrenergic activity andisoproterenol to overcome the b blockade. Since a biphasic response is possible,monitor the patient for a minimum of four hours, longer in cases of moresevere anaphylaxis.
Patients who are at risk for anaphylaxis should wear a Medic Alert braceletor similar device at all times, with medical information about their condition.This information will expedite diagnosis and appropriate treatment.
Table 5 summarizes how to manage the acute attack of anaphylaxis.
Long-term management. The life-threatening nature of anaphylaxis makesprevention the cornerstone of therapy. If the cause is not clear, promptlyinitiate an evaluation since avoiding the specific allergen is the bestway to prevent a lethal recurrence. Those at risk for more severe anaphylacticreactions must be educated on how to avoid all forms of the allergen andjust how severe a reaction can be. Direct your educational efforts at thepatient, family, school personnel, and other caretakers so that they understandthe potential severity and scope of the problem.
When the allergen cannot be avoided, other preventive measures shouldbe considered, including venom immunotherapy (in all patients with provenHymenoptera anaphylaxis), drug desensitization protocols (in patients withanaphylactic sensitivity to a necessary drug), and pretreatment protocolsfor patients with systemic reactions to radiocontrast media.
Table 6 summarizes the long-term management strategies for anaphylaxis.
Anaphylaxis usually is not difficult to recognize and prompt administrationof epinephrine is lifesaving. Once the initial reaction is under control,finding its cause and instituting a strategy to prevent future episodesis of prime importance. Prevention is the key to long-term management ofthe child who is prone to anaphylaxis.
DR. BECK is Associate Clinical Professor of Pediatrics, Texas Tech UniversitySchool of Medicine, Lubbock. She is a member of the Speakers Bureaus atAstra, Glaxo Wellcome, Schering Key, and Wallace.
DR. BURKS is Professor of Pediatrics, University of Arkansas for MedicalSciences, Arkansas Children's Hospital, Little Rock.
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