ANAPHYLAXIS

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ALLERGY AND IMMUNOLOGY

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00954543 /98 $8.00

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ANAPHYLAXIS Diagnosis and Treatment Theodore M. Freeman, MD

In 1901, Portier and Richet6studied immunization of animals against sea anemones toxins. At that time, the Prince of Monaco was an avid supporter of scientific research, and the initial studies were done in the Mediterranean Sea on his yacht.* Dr Portier and Dr Richet initiated their studies looking at the stings from Portuguese Man-0-Wars, but in completing their studies they finished using sea anemones, which were more readily available to them when they returned to Paris.6 They were examining the immune response to the toxins and they discovered something unexpected: While endeavoring to determine its toxic dose we soon discovered that some days must elapse before fixing it; for several dogs did not die until the fourth or fifth day after administration, or even later. We kept those which had been given a dose insufficient to kill, in order to carry out a second investigation upon them when they had completely recovered. At this point an unforeseen event occurred. The dogs which had recovered were intensely sensitive, and died a few minutes after the administration of small doses.. . . . . . . . These two factors-a. increased sensitivity to a poison after previous injection of the poison, and b. an incubation period necessary for this state of The opinions and assertions contained herein are the private views of the author and are not to be considered as official or as reflecting the views of the Department of Defense or other departments of the US Government. This article was supported entirely by the US Air Force. The author has no other corporate or institutional affiliations. *The principality of Monaco recently issued a stamp featuring the Prince of Monaco, Drs Portier and Richet, a Portuguese Man-0-War, the yacht, and the year 1901.

From the Wilford Hall Medical Center, Lackland Air Force Base, Lackland, Texas PRIMARY CARE VOLUME 25 -NUMBER 4 * DECEMBER 1998

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increased sensitivity to develop-constitutethe two essential and sufficient conditions for anaphylaxis?

Dr Richet, who was the senior member of the partnership, received the Noble prize in medicine or physiology for this discovery in 1913.6They coined the term anaphylaxis to describe this. This came from the Greek a meaning ”not” or “against” and phylaxis derived from the Greek word phylaxis meaning ”a guarding” or “protection” so aphylaxis was against protection or the opposite to protection. Dr Portier and Dr Richet added the extra syllable making it anaphylaxis because aphylaxis was dysphonic. Therefore, anaphylaxis means a detrimental reaction to a substance.

MECHANISM What is the mechanism of anaphylaxis? By definition, anaphylaxis is an IgE-mediated release of mast-cell products. A mast cell basically is a cell that is full of chemicals and has receptors on its surface for a variety of proteins that may serve as initiating complexes. In particular, it has receptors for IgE on its surface. When individuals have been exposed previously to an antigen, their immune system may develop specific IgE to that antigen. If they have and they are subsequently exposed to that antigen again, and if the specific IgE is in high enough concentration, the antigen may cross-link the IgE on the surface of the mast cells. The mast cell will become activated and begin to release its chemicals. There are a wide variety of chemicals released by mast cells that include substances such as histamine, leukotrienes, C,, D,, and E, (LTC,, LTD,, LTE,), eosinophil chemotactic factor of anaphylaxis (ECF-A), neutrophil chemotactic factor of anaphylaxis (NCF-A),and platelet activating factor (PAF).2These substances are vaso-active, that is, they lead to smooth muscle spasm, bronchospasm, mucosal edema and inflammation,and increased capillary permeability, which leads to the symptomotology associated with anaphylaxis.2The mast cell also may release additional mediators that may not have importance to the symptomotology, but may be important for making a diagnosis. In particular, tryptase, an enzyme that is not vasoactive, is released by mast cells. Mast cells also may be stimulated to produce new mediators, which may be released over the subsequent hours that lead, in some cases, to biphasic reactions or late-phase reactions after the initial anaphylactic symptoms.* In addition, besides the IgE-specific mechanism, mast cells can be activated by other mechanisms. These include immunologic mechanisms, such as the development of complement-mediated (immune complex) anaphylatoxins, which occurs with IgG aggregates from intravenous immunoglobulin (IVIG), or with antibodies to red blood cells from mismatched blood transfusions.2 Nonimmunologic mechanisms also may be responsible for mast-cell activation? Many of these are caused by direct mast-cell releasers. Direct activators of mast cells include medications such as opiates and narcotics, radioconstrast media, dexstrans, neuro-

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muscular blockers, and other low molecular weight chemicals.2By convention, if a mast cell is activated by IgE, specifically, it is considered anaphylaxis. If it is activated by non-IgE-mediated mechanisms, then it is called anaphylactoid. DIAGNOSIS

A typical presentation of anaphylaxis is the rapid onset of symptomotology. Although anaphylaxis may start as late as 24 hours after antigen exposure, it nearly always starts within minutes and sometimes within seconds of re-exposure to an antigen to which the patient has previously been exposed. Symptomotology can be very benign. It can consist of a fear of impending death, a metallic taste in the mouth, or a feeling of weakness or dizziness. More severe symptoms include pruritus of eye, conjunctival infusion, and lacrimation. If the skin is involved, it may include erythema, flushing, pruritis, angioedema, and urticaria of the skin. There can be pruritis, congestion, sneezing, and rhinorrhea of the nose, as well as swelling of the lips and tongue. The symptomotology can be very severe, leading to confusion, seizures, and loss of consciousness, or if the gastrointestinal (GI) tract is involved, nausea, vomiting, cramping, and diarrhea may develop. The upper airway may be involved with stridor, angioedema and swelling, and the lower airway may be involved with dypsea, wheezing, and respiratory arrest. The cardiovascular system can be involved with tachycardia, hypotension, arrhythmia, and complete cardiovascular collapse. Death does occur. What is most important to remember about the symptomotology of anaphylaxis is the rapid onset and the rapid progression of the symptoms. Symptomotology may start with purely subjectivesymptoms that rapidly progress through upper or lower airway obstruction, to cyanosis, syncope, convulsions, and death. This progression can occur over minutes. This is extremely important to remember, as it has important implications to the acute therapy of anaphylaxis. Anaphylaxis should be differentiated from a variety of other potential causes or complexes that look like anaphylaxis, such as those listed below. Differential Diagnosis of Anaphylaxis Vasovagal reactions Hereditary angioedema Serum sickness Systemic mastocytosis Pheochromocytoma Carcinoid syndrome This article addresses each of these syndromes briefly. Vasovagal reactions occur in individuals who are very anxious over a particular situation. For example, some people have needle phobias, and in receiving an injection, they may rapidly develop a light-headed feeling and become nonresponsive. These individuals are having a vasovagal response and have a slow, steady, strong pulse. Individuals with anaphylaxis often have a weak,

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thready, rapid, pulse. This serves as a differentialpoint between vasovagal reactions and anaphylaxis. Hereditary angioedema is angioedema usually of the lips, tongue, or upper airway, but may be associated with angioedema of the GI tract leading to cramping and abdominal pain, nausea, and diarrhea. It often develops after some trauma, such as a dental procedure. This can be differentiated from anaphylaxis by laboratory findings and because it does not manifest the other typical anaphylactic symptoms. Complement levels, in particular C,, are low in hereditary angioedema. Serum sickness is a clinical syndrome in which individuals on exposure to a particular antigen develop symptomotology of arthralgias associated with urticaria, fever, and elevated sedimentation rates. These symptoms often occur 7 to 10 days after the antigen exposure because of formation of immune complexes. On future exposures, reactions may occur within 2 to 3 days. This timing is different from that of anaphylaxis; Anaphylaxis usually is not associated with fever or elevated sedimentation rates. The symptomotology for systemic mastocytosis looks exactly like anaphylaxis because the same agent, mast cells, are involved. In this case, there is an unusual proliferation of mast cells either in the skin (urticaria pigmentosa) or in the bone marrow. The differential occurs in that symptoms are not associated with a particular antigen exposure for systemic mastocytosis. Pheochromocytoma and carcinoid are both neoplastic syndromes that are associated with the release of vasoactive substances and that often lead to elevated blood pressure and flushing. The specific agents released are epinephrines, norepinephrines, and vanillylmandelic acid (VMA) for pheochromocytoma and 5-HIAA or serotonin for carcinoid syndrome. Measures of the these specific mediators in the urine differentiates them from anaphylaxis. In some cases, it still is very difficult to make a diagnosis of anaphylaxis. This may be because a specific agent is not clearly related to the symptoms or, alternatively, the symptoms may have occurred and been treated and resolved. In either case, the way to make sure that a mastcell-mediated event occurred is to measure the mediators that have been released. It might be expected that histamine is the right mediator to measure in the blood; however, it has a very short half life in the serum that may last for only minutes. Consequently, it is very difficult to actually catch an elevated histamine level in the serum. Therefore, the best mediator to measure and thus implicate mast cells is tryptase.I8As mentioned before, it is released by the mast cells during anaphylaxis, but instead has a serum half life of 2 hours after maximal levels are detected.I8Therefore, it may serve to verify mast-cell-released mediators that are involved in a particular episode. TREATMENT

There is one absolutely essential point to remember about the acute therapy of anaphylaxis. As mentioned above, anaphylaxis can begin with

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very subjective symptomotology that very rapidly moves into severe lifethreatening symptomotology. Many times, because of its initial presentation, anaphylaxis is taken less seriously, and supplemental medications are used to treat the symptoms. Anaphylaxis must be treated with epinephrine as soon as the diagnosis is suspected. The dose for epinephrine is aqueous 1:lOOO 0.3 mL to 0.5 mL subcutaneously. In children, the dose is aqueous 1:lOOO 0.01 mL/kg up to a max of 0.3 mL. Individuals suffering from anaphylaxis should be treated by establishing and maintaining an adequate airway, and then supplemental therapy may be given. This may include delivery of oxygen, use of antihistamines (both HI and HJ, use of steroids, and use of beta adrenergics for bronchospasm of the lower airway. None of these supplemental medications should take the place of epinephrine. In addition, after any acute episode seen in the ER or seen in the physician’s office where epinephrine has been delivered, the patient should be offered home epinephrine (either epi pens or anaphylaxis kits) and instructed in their use. They should also be instructed to obtain medical alert bracelets. If the patient is exposed to a particular agent again, he or she can initiate the treatment or, if they are found unresponsive, a good Samaritan can offer help based on this information. There is a special case that occurs in the treatment of anaphylaxis. pblockers are commonly-used medications (hypertension, antimigraine, antianxiety).Individuals who use P-blockers may not respond completely or fully to the epinephrine delivered for anaphylaxis, in which case the alternative therapy is to use glucagon at a dose of 5 pg/min to 15 pg/min intravenously.” SPECIAL CASES

In examining the potential antigens that may lead to anaphylaxis, the total number of agents that could cause anaphylaxis is essentially equivalent to the total number of antigens to which an individual’s immune system responds. This has been estimated to equal approximately the total number of potential antigens in the universe. Practically, what is seen are some common agents. Occasionally, there are some more interesting agents, which are described below. Food

Foods are fairly common agents for causing anaphylaxis. The estimated risk in the general population is 1% to 2%.1° In those having food allergies, the most common agents include peanuts, tree nuts, shell fish, fish, milk, eggs, soy, and wheat.I0 Individuals who develop anaphylaxis to these agents may sometimes have life-long problems with them.loThe mostly likely life-long agents include peanuts, nuts, and shell fish.1° The only available treatment is to avoid these agents. This is not a minor problem; death has occurred in individuals who have food allergies.*OThe most likely presentation is when someone, who goes out to eat, explains his or

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her food allergy, is assured that the food does not contain a particulai agent, unfortunately finds the agent in the order. The patient either has forgotten his or her epinephrine or denies that anaphylaxis is occurring, because he or she assumes there has been no exposure to the agent, and, therefore, epinephrine is not used during the initial symptomotology. In one case, a peanut-allergic patient ordered chili that had been thickened with peanut butter and died.20 Hymenopteria Sensitivity

Hymenoptera are a frequent cause of anaphylaxis in the United States. The general population at risk approaches 1%.loFifty deaths are attributed to hymenoptera anaphylaxis every year in the United States.Io The most frequent agent in the southeast United States is the imported fire ant (IFA).7Other agents throughout the United States include wasps, yellow jackets, and honey bees. Individuals who have suffered anaphylaxis after hymenoptera sting are at 50%to 60% risk that future stings also will result in anaphylaxis.8Hymenoptera prophylaxis is available. Venom or whole-body-extract immunotherapy in the case of IFA has been shown to reduce significantly future anaphylaxis after hymenoptera stings? In appropriately selected patients, the risk for future anaphylaxis on these therapies is reduced to the 2% to 3% range.8 Drug-related Anaphylaxis

Drug reactions are a very frequently described problem in the United States. Many drugs can cause anaphylactoid type symptoms through nonIgE mediated mechanisms. In addition, frequently used agents, particularly antibiotics, and especially penicillin, can lead to anaphylaxis.16Penicillin and local anesthetics can be evaluated for an IgE-mediated mechanism with skin testing. Unfortunately, the preferred management is to avoid or substitute for any particular agent that has caused symptomotology. If an agent is absolutely essential to treat a patient, desensitization may be attempted. Basically, a dose or more dilute than the final dosing concentration is given.I6 Every 20 to 30 minutes, an increased dose is delivered.I6If symptoms of anaphylaxis occur, treatment with epinephrine is given. The protocol is continued when symptoms resolve until a therapeutic range of the medication has been reached.'6 Latex

Latex is becoming a more frequent producer of anaphylaxis. Individuals most at risk include manufacturers of latex products, health care workers, and patients who had early or recurrent surgical or medical problems in which they were exposed to latex frequently (e.g., patients with spina bifida).1,12,14 One of the interesting things about latex is that

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it has many cross-reactivities with foods, in particular, avocados, bananas, and chestnuts. The only therapy that can be attempted for latex allergy at this time is to use latex-free products. This is especially important for health care workers who have become latex allergic. Unfortunately, it is nearly impossible to provide a completely latex-free environment in the health care setting, as many latex particles will become airborne on the powder that is found in latex gloves. Consequently, health care workers who are allergic to latex may be forced to change professions. Exercise

Another interesting cause of anaphylaxis is exercise. Exercise has been associated with other syndromes that need to be differentiated from the exercise-induced anaphyla~is.'~ These include cholinergic urticaria and exercise-induced bronchospasm (exercise-induced asthma). The differential is that if an individual exercises and develops urticaria alone (multiple 1 mm- to 2-mm raised lesions), this is probably cholinergic urticaria. When the individual develops bronchospasm alone, that is probably exercise-induced bronchospasm (EIB). If they develop the urticaria and bronchospasm, then it is probably exercise-induced anaphylaxis (EIA). One of the interesting facts about exercise-induced anaphylaxis is that it often requires a cofactor of a particular food, such as celery, carrots, or wheat.13Individuals who have these additional characteristics can exercise safely as long as they don't eat that particular food and can eat that particular food as long as they don't exercise within a few hours of eating that food. Therapy for these individuals then involves avoiding the exposure to both agents in the same time frame. Individuals who have pure exercise anaphylaxis should never exercise alone, should always have epinephrine kits when they go out to exercise, and the person they are exercising with should be aware of their problem. Idiopathic Anaphylaxis

There is a small group of people who suffer anaphylaxis and, despite the best clinical detective efforts, the agent remains undiscovered. These individuals are assigned a diagnosis of idiopathic anaphylaxis. It is very rare and is a diagnosis of exclusion. If individuals suffer infrequent episodes (less than six episodes per year), individual episodes can be treated when they occur.17If individuals suffer frequent episodes (greater than six per year), they may require daily high-dose steroids to manage their anaphyla~is.'~ Postimmunotherapy Anaphylaxis

Perhaps the most frequent cause of anaphylaxis seen in any Allergy/ Immunology clinic is postimmunotherapy (IT) anaphylaxis. Usually, an-

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aphylaxis rates run between 3 and 6 per 1000 injections. Generally, these are mild reactions and quickly respond to appropriate epinephrine therapy; however, prior studies have shown that deaths occur after IT at a rate in both the United States and Great Britain of sometimes more than one per ear.^,'^ Clearly, IT is not a benign therapy that should be delivered at home, and guidelines from the American Academy of Allergy, Asthma, and Immunology suggest that it be given only in a physician’s office, under supervision, and with appropriate resuscitation and therapy for anaphylaxis available. The guidelines also stipulate that individuals receiving such IT should receive it and wait for at least 20 to 30 minutes postinjection in the physician’s o f f i ~ e . ~ CONCLUSION

Anaphylaxis is a clinical syndrome that can be caused by many different agents. The treatment acutely consists of injections of epinephrine. Prophylactically, in most cases, the only therapy that is available is to avoid the agent to which the individual is allergic. Occasionally, a specific IT may be offered, such as is the case with hymenoptera. In some cases, desensitization for a drug that is absolutely required can be attempted. All individuals should be issued anaphylaxis kits and given information on the purchase of medical alert bracelets, especially when the agent is unavoidable or when individuals may be exposed without their knowledge. References 1. American College of Allergy, Asthma and Immunology: Special bulletin on latex allergy, 1996 pp 1 4 2. Atkinson TP, Kaliner MA: Anaphylaxis. Med Clin Nor Am 76:841-855,1992 3. Committee on Safety of Medicine: Desensitizing vaccines. BMJ 293:948,1986 4. Douglas DM, Sukenick E, Andrade WP et al: Biphasic systemic anaphylaxis: An inpatient and outpatient study. J Allergy Clin Immunol93(6):977-985,1994 5. Executive committee American Academy of Allergy Asthma & Immunology, waiting time after allergen skin testing and immunotherapy (position statement). J Allergy Clin Immunol79:526-527,1988 6. Cohen MD, Samter MD (eds): Excerpts from Classics in Allergy, ed 2., Symposia Foundation, Carlsbad, CA 1992, pp 56-57 7. Freeman TM: Epidemiology of hymenoptera hypersensitivity in IFA endemic area. Ann Allergy Asthma Immunol78369-372,1997 8. Freeman TM. Insect and Fire Ant Hypersensitivity: What the Primary Care Physician should know. Compr Ther 233843,1997 9. Freeman TM, Hylander R, Ortiz A, Martin ME: IFA immunotherapy: Effectiveness of whole body extract, J Allergy Clin Immun 90215,1992 10. Gold M, Sussman G, Loubser M, et al: Anaphylaxis in schools and other childcare settings. AAAAI Anaphylaxis Committee statement, Academy News, 1997, pp 17-18 11. Jacobs RL, Rake GW, Fournier DC,et a 1 Potentiated anaphylaxis in patients with druginduced beta-adrenergic blockade. Journal of Allergy and Clinical Immunology 68:125127,1981 12. Kaczmaret RG, Silverman BG, Gross TP, et a 1 Prevalence of latex-specificIgE antibodies in hospital personnel. Ann Allergy Asthma Immunol7651-56,1996

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13. Kidd JM, Cohen SH, Sosman AJ, et al: Food-dependent exercise-induced anaphylaxis. J Allergy Clin Immunol71:407411,1983 14. Konz KR, Chia JK, Yump UP, et a1 Comparison of latex hypersensitivity among patients with neurologic defects. J Allergy Clin Immunol95:950-954, 1995 15. Lockey W, Benedict LM, Turketaub PC, et al: Fatalities from immunotherapy and skin testing. J Allergy Clin Immunol79:660-677, 1987 16. Patterson R, Deswarte RD, Greenberger PA, et a 1 Drug allergy in protocols for management of drug allergies. Allergy Proceedings 15236-264, 1994 17. Patterson R, Stoloff RS, Greenberger PA, et al: Algorithms for the diagnosis and management of idiopathic anaphylaxis. Annals of Allergy 71:4044,1993 18. Schwartz LB, Bradford TR, Rouse C, et al: Development of a new, more sensitive immunoassay for human tryptase: Use in systemic anaphylaxis. J Clin Immunol 1 4 1 9 s 204,1994 19. Sheffer AL, Soter NA, McFadden ER, et a 1 Exercise-induced anaphylaxis: A distinct form of physical allergy. J Allergy Clin Immunol71(3):311-316, 1983 20. Yunginger JW, Sweeney KG, Sturner WQ, et a1 Fatal food-induced anaphylaxis, JAMA 260:145G1452,1988

Address reprint requests to Theodore M. Freeman, MD Col, USAF, MC Wilford Hall Medical Center 59th Medical Wing/PSMA 2200 Bergquist Drive, Suite 1 Lackland AFB TX 78236-5300