INSECT STING ALLERGY: A MODEL FOR IMMEDIATE HYPERSENSITIVITY REACTIONS ROBERT E. REISMAN, M.D. BUFFALO
INTRODUCTION Immediate hypersensitivity reactions are mediated by IgE antibodies bound to mast cells in tissue and basophils in blood. The bridging of two antibodies by antigen leads to release of preformed and newly generated mediators and resulting clinical symptoms. These clinical symptoms usually occur immediately, within minutes of antigen exposure, and may reoccur four to six hours later, the so called late onset reaction. Classical examples are common allergic problems such as anaphylaxis, rhinitis, asthma and urticaria. Insect sting allergy is another classic example of an immediate hypersensitivity reaction. It is a major medical problem with estimates of 50 deaths per year in this country caused by insect sting anaphylaxis (1) and the likelihood that other instances of sudden death are due to unrecognized allergic reactions. The morbidity is extensive and leads to substantial anxiety, panic and modification of lifestyle. The causative agents, members of the order Hymenoptera, are the honeybee, yellow jacket, hornet, and wasp. In addition, the fire ant which is a non-winged Hymenoptera, is responsible for numerous reactions in the Southeastern United States and along the Gulf Coast (2). The major advances which have occurred in recent years in understanding of insect sting allergy have occurred primarily because of two factors; the availability of purified insect venoms for diagnosis and treatment and the development of methodology for measurement of immunologic markers, serum venom specific IgE, the immunologic mediator of allergy and serum venom specific IgG, the immunologic mediator of immunity. The clinical applications of measurement of these immunologic parameters have resolved the majority of the diagnostic and therapeutic issues. In addition, there are numerous analogies which have application to other immediate hypersensitivity reactions such as allergic rhinitis (hay fever), food allergy and drug allergy.
From the Division of Allergy and Immunology, Departments of Medicine and Pediatrics, State University of New York at Buffalo, Buffalo, New York. 7
8
ROBERT E. REISMAN
INSECT STING REACTIONS The usual or normal reaction following an insect sting is local pain, erythema and swelling. In contrast to insect bites, insect stings always cause pain. This normal reaction usually subsides in 1 to 2 hours and does not require treatment other than local applications of cold compresses and analgesics. More extensive local reactions may occur following an insect sting, with swelling extending from the sting site over a large area, often peaking at 48 hours and lasting as along as 1 week. If severe, this reaction is sometimes accompanied by fatigue and nausea. The usual medical treatment for large local reactions is aspirin and antihistamines. If the reaction is extensive and disabling, steroids, such as prednisone, 40 mg daily for 2 to 3 days, are very helpful in reducing the local swelling. The most serious reaction is insect sting anaphylaxis. This reaction affects approximately 0.4% of the population. These reactions can occur at any age. Most have occurred in individuals under the age of 20 years, with a male-to-female ratio of 2:1. In all likelihood, the incidence is a reflection of exposure rather than of any specific age or sex predilection. Approximately one third of individuals who have had systemic reactions from insect stings have a personal history of atopic disease. Reactions may occur from stings on any area of the body (3, 4, 5). The clinical symptoms of anaphylaxis vary from patient to patient and are typical of anaphylaxis from any cause. The most common symptoms are dermal: generalized urticaria, flushing and angioedema. More serious symptoms are respiratory and cardiovascular. Upper airway edema involving the pharynx and epiglottis and circulatory collapse with shock and hypotension have been responsible for fatalities. Other less common symptoms include diarrhea and uterine contractions. In most patients these symptoms occur within 15 to 20 minutes after a sting, although, occasionally, reactions can occur as long as 72 hours after the sting. Clinical observations suggest that the sooner the symptoms occur, the more severe the reaction. Severe anaphylaxis can occur in all age groups. Most deaths due to insect sting anaphylaxis occur in adults. The presence of cardiovascular disease or other pathologic changes associated with age may be responsible for the increased incidence of fatalities in adults, who may have less tolerance for the fairly significant biochemical and physiologic changes that accompany anaphylaxis. Most patients who have severe anaphylactic reactions have no warning of their sensitivity. As a rule, prior stings have been tolerated with no or little difficulty. The use of beta adrenergic antagonists is associated with more severe reactions.
INSECT STING ALLERGY
9
Diagnosis The diagnosis of insect sting allergy is confirmed by the positive immediate skin test reaction, a wheal and flare reaction which occurs 10-15 minutes after a puncture or intradermal test with diluted insect venoms. Individual honeybee, yellow jacket, yellow hornet, bald faced hornet and wasp venoms are available for the diagnosis and treatment of insect sting allergy. Current recommendations are to skin test individuals with relevant histories with appropriate dilutions of each of the available Hymenoptera venom preparations. An immunologically specific reaction is elicited by venom concentrations equal to or less than 0.1 mcg per ml to 1.0 mcg per ml. Measurement of serum venom specific IgE by the radioallergosorbent test (RAST) also can be done but this test is not as sensitive as the skin test and may be negative in as many as 20% of individuals who are skin test positive. Natural History In recent years, much has been learned about the natural history of insect sting allergy (6). Patients have been observed who: (1) had a history of anaphylaxis after an insect sting, (2) had venom specific IgE documented by positive skin tests or in the serum by the RAST at the time of evaluation, (3) did not receive venom immunotherapy (discussed below) and (4) had a subsequent insect sting. The results of these studies may be summarized as follows: (1) Overall in an unselected population approximately 60% of individuals with prior allergic sting reactions have re-sting allergic reactions. (2) The re-sting reactions are more likely to occur in adults than in children. (3) The occurrence of more severe anaphylactic symptoms, such as shock, hypotension and loss of consciousness, is a high risk factor for repeat sting reactions. (4) Insect sting allergy is a relatively benign process and self limiting for children with urticaria as the only allergic symptom and may be benign for adults with similar mild reactions. Similar analogies to the self limiting nature of the clinical disease and the dichotomy between the continued presence of IgE antibody as detected by a positive skin test and the lack of clinical symptoms, also have been observed in patients with hay fever, food allergy, and drug allergy. It is not unusual for patients who no longer have clinical symptoms of ragweed hay fever, to retain their positive skin test reaction for many years. Children with certain food allergies such as egg and milk retain their positive skin tests, but lose clinical sensitivity as they grow older. There have been reports of a few patients who tolerate penicillin in the presence of positive skin tests. In this situation, if the drug is necessary, it is usually administered in a desensitization protocol.
10
ROBERT E. REISMAN
Therapy Individuals with a history of an acute allergic reaction following an insect sting and positive venom skin tests are considered at risk for subsequent sting reactions. Therapeutic recommendations include measures to minimize exposure to insects, the availability of emergency medication for medical treatment of anaphylaxis (epinephrine) and venom immunotherapy. As noted above, children who have had dermal symptoms only, have a benign prognosis and do not require venom immunotherapy. The documentation that adults with a similar reaction have a similar benign prognosis has not been as well substantiated. All patients who have had severe symptoms of anaphylaxis and have positive venom skin tests should receive venom immunotherapy regardless of the interval since the last sting reaction. These criteria are summarized in Table I. The details of venom immunotherapy have been reasonably defined in recent years and are outlined on Table II. The selection of venom is based upon knowledge of the culprit insect and the skin test reaction. When the identity of the culprit insect is not known and there are multiple positive skin test reactions, which is not an uncommon problem because of cross sensitivity between venoms, it may be necessary to administer multiple venoms. As a rule venom immunotherapy is initiated at doses of 0.1 to 1 mcg and gradually increased to a top maintenance dose ranging between 50 to 100 mcg. Therapy is then continued once monthly and the interval extended to six or eight weeks after the first or second year. The results of venom immunotherapy are almost 100% TABLE 1 Indications for Venom Immunotherapy in the Presence of Positive Skin Tests* Venom
Reaction
Immunotherapy
No Normal-transient pain, swelling No Large Local Anaphylaxis-severe Yes Children Yes Adults Anaphylaxis-dermal reaction only No Children Yes-under review Adults Yes Toxic** * Venom immunotherapy is not indicated in individuals with negative venom skin tests. ** Toxic reactions are due to multiple stings. The symptoms mimic symptoms of anaphylaxis. Patients may become sensitized and are then at risk for anaphylaxis from subsequent single stings.
11
INSECT STING ALLERGY TABLE 2 Details of Venom Immunotherapy Individual venom whenever possible Venom Selection based upon history and skin test reactivity 0.1 to 1.0 mcg Initial Dose 50 mcg Top Dose 4 weeks; extend to 6-8 weeks after 1 year Maintenance Interval Duration of Therapy a) 3 to 5 years; depends upon nature of anaphylaxis or
b) Negative skin test reaction
effective (7, 8). A number of studies have shown a very low re-sting reaction rate in treated patients. Successful venom immunotherapy is associated with the development of venom specific IgG, although the absolute titers of these antibodies do not appear to be a critical indicator of immunity. Criteria for the duration of venom immunotherapy are still evolving. Suggested criteria include the conversion to a negative skin test (9), the fall in serum IgE antibody titer to insignificant levels (10) and a finite period of time three to five years (11, 12, 13, 14). From a practical viewpoint it would appear that three years of therapy is sufficient for patients who have had mild to moderate symptoms of anaphylaxis. Patients who have had severe anaphylaxis may require longer periods of therapy to assure continued protection. The immunologic responses to venom immunotherapy are similar to those found after treatment with other types of allergenic extracts. IgG antibodies appear to play a protective role in successful desensitization of patients with drug allergies, such as penicillin. It is more difficult to assess the role of these antibodies in classic treatment of inhalant allergy, (rhinitis, asthma) but in general elevated titers are associated with improved clinical responses. Insect sting allergy reflects many of the typical clinical and immunologic features of other types of immediate hypersensitivity reactions. Unresolved issues persist such as factors influencing the development of insect sting allergy and the persistence of immunologic reactivity (IgE antibody) in the absence of clinical sensitivity. REFERENCES 1. Barnard JH: Studies of 400 Hymenoptera sting deaths in the United States. J Allergy Clin Immunol 1973; 52: 259 2. Stafford CT, Hoffman DR, Rhoades RB: Allergy to imported fire ants. South Med J 1989; 82: 152
12
ROBERT E. REISMAN
3. Brown H, Bernton HS: Allergy to Hymenoptera. Arch Inter Med 1970; 125: 665 4. Frazier CA: Allergic reactions to insect stings: A review of 180 cases. South Med J 1964; 57: 1028 5. Mueller HL, Schmid WH, Rubinsztain R: Stinging insect hypersensitivity: A 20 year study of immunologic treatment. Pediatrics 1975: 55: 530 6. Reisman RE: Natural history of insect sting allergy: Relationship of severity of symptoms of initial sting anaphylaxis to re-sting reactions. J Allergy Clin Immunol 1992; 90: 335 7. Valentine MD: Insect venom allergy: Diagnosis and treatment. J Allergy Clin Immunol 1984; 73: 299 8. Reisman RE, Livingston A. Venom immunotherapy: Ten years of experience with administration of single venoms and 50 jtg maintenance doses. J Allergy Clin Immunol 1992; 89: 1189 9. Golden DBK, Johnson K, Addison BI, et al: Clinical and immunologic observations in patients who stop venom immunotherapy. J Allergy Clin Immunol 1986; 77: 435 10. Reisman RE, Lantner R: Further observations on discontinuation of venom immunotherapy: Comparisons of patients stopped because of a fall in serum venom-specific IgE to insignificant levels with patients stopped "prematurely" by self choice. J Allergy Clin Immunol 1989; 83: 1049 11. Golden DBK, Kwiterovich KA, Kagey-Sobotka A, et al: Discontinuing venom immunotherapy (VIT): Determinates of clinical reactivity [abstract]. JAllergy Clin Immunol 1988; 81: 262 12. Schuberth KC, Kwiterovich KA, Kagey-Sobotka A, et al: Starting and stopping venom immunotherapy (VIT) in children with insect sting allergy [abstract]. J Allergy Clin Immunol 1988; 81: 200 13. Mueller U, Berthold E, Helbling A: Honey bee venom allergy: Results of a sting challenge one year after cessation of successful venom immunotherapy in 86 patients. J Allergy Clin Immunol 1991; 87: 702 14. Hauggard L, Norregaard OFH, Dahl R: In-hospital sting challenge in insect venom allergic patients after discontinuation of venom immunotherapy. J Allergy Clin Immunol 1991; 87: 699
DISCUSSION Middleton, Buffalo: A question occurred to me this morning that I don't think I've ever asked you before and that is, is anything known about the role of the eosinophil in this type of Hymenoptera sensitivity. I wondered if the neurologic symptoms could be related to the eosinophil-derived neurotoxin and the so-called Gordon phenomenon. Reply: The eosinophil is not involved. As I indicated, the majority of patients who have sting reaction are non-atopic, and they don't have hay fever or asthma, and would not be expected to have eosinophils. I don't think anybody understands the nature of the neurologic reactions that rarely occur after insect stings. We have studied two people who did have antimyelin antibodies. Not knowing what the Gordon phenomena is, I'm sorry I can't
answer that further. Douglas, Princeton: I have two practical questions. One is, you discussed active immunization, which seems to be very effective. Is there any information on passive immunization with specific IgG antibodies, for instance, in a child who is severely allergic so he or she can get some protection early? Secondly, in the longer term, do you have any idea what is going to happen five or 10 years after stopping immunotherapy? Do you need booster injections? Is there a possibility that as the IgG antibodies fall, that IgE will rebound? Is there any information on that?
INSECT STING ALLERGY
13
Reisman: Obviously, that information is accruing. If one looks back to the old days of treatment of this disease with an ineffective antigen and realizes we were looking at the natural history of the disease, it is clear that patients lost their allergy. That is, individuals who have had reactions in childhood, and never were treated effectively, may not react to insect stings as adults. So I think it is a self-limiting disease for many people. To date, from our studies that go back 15 years, we have not seen a return of allergy in the majority of individuals who stopped treatment. Have you studied the antibody profile of those individuals? Reisman: IgE and IgG tend to fall off. That is, if you are not exposed to venom, the antibodies tend to decrease. The IgG falls off very quickly, and that is one of the problems after stopping treatment. IgE antibodies, as you know, can persist for a long period of time, fall off more slowly and eventually, disappear. Of course, there are people who retain some degree of IgE antibodies and still don't react to stings for reasons not really understood. This dichotomy between immunologic and clinical reactivity remains a major problem. Your other question concerned passive immunization. That's a very interesting question. Hyperimmune gamma globulin can be obtained from bee keepers. Bee keepers, as I indicated earlier, are very immune. They have high levels of IgG because they are stung repeatedly. If you passively administer this IgG antibody, people are protected for a short period of time, roughly about three weeks. The original studies were done by Lessof and Lichtenstein in England. They showed that passive administration of IgG did protect allergic individuals against reactions from venom exposure. There had been attempts to utilize passive immunization to protect patients immediately while initiating active immunization and in individuals who had reactions to venom immunization. Venom immunization involves giving gradually increasing doses of venom until you reach an adequate maintenance protection dose. There are some patients who react to exquisitely small venom doses. Passively administered IgG might prevent some of these reactions and allow active immunization to proceed. Fortunately, this approach is rarely required. Odell, Salt Lake City: This is also a practical question. Do you use a specific venom from the species of bee that the individual is allergic to, or a mixture of venom from all bees? Reisman: We try very hard to use venom of a specific species. We test, as a rule, with the commercial venoms, which are hornet, yellow jacket, wasp, and honeybee. One of the problems is that there is extensive cross reaction, particularly among the vespids, yellow jacket, hornet and wasp. As much as possible, based on history and knowledge of the culprit stinging insect, we try to individualize venom therapy. When this is impossible, it may be necessary to administer multiple venoms. Horwitz, Philadelphia: I'm very interested in this, both from the point of view of a physician and also as a patient. I've been using prednisone, or steroids, and that has made a great deal of difference in my life as far as this is concerned. I got advice about these long term immunizations and I just decided that I'd wait until I got stung and then take some prednisone. I had no trouble at all. You didn't mention anything about the steroids. Do you use them at all? Reisman: Time didn't allow me to discuss every aspect of insect sting allergy. Individuals at risk of a severe sting reaction are taught to administer epinephrine. Epinephrine is the drug of choice for any severe anaphylactic reaction. It comes in pre-packaged syringes and in a more convenient form, marketed as Epi Pen. The drug of choice for an immediate allergic reaction is epinephrine, which is given along with antihistamines. Prednisone is not effective for an immediate allergic reaction. It is effective for treatment of large local reactions, such as serum sickness reaction. McCarty, Milwaukee: My question was the same as Dr. Horwitz's. Whether a little pop of epinephrine at the time of the bite might be more cost effective?
14
ROBERT E. REISMAN
Reisman: The difference is that we can almost guarantee someone full immunity by giving them venom injections. Epinephrine should ameliorate the reaction, but there still have been very severe reactions in people taking epinephrine. Secondly, if you ever talked to people for whom you have prescribed epinephrine, after the first few months, they usually don't carry it with them all the time. You never know when a sting is going to occur.
INTRODUCTION Immediate hypersensitivity reactions are mediated by IgE antibodies bound to mast cells in tissue and basophils in blood. The bridging of two antibodies by antigen leads to release of preformed and newly generated mediators and resulting clinical symptoms. These clinical symptoms usually occur immediately, within minutes of antigen exposure, and may reoccur four to six hours later, the so called late onset reaction. Classical examples are common allergic problems such as anaphylaxis, rhinitis, asthma and urticaria. Insect sting allergy is another classic example of an immediate hypersensitivity reaction. It is a major medical problem with estimates of 50 deaths per year in this country caused by insect sting anaphylaxis (1) and the likelihood that other instances of sudden death are due to unrecognized allergic reactions. The morbidity is extensive and leads to substantial anxiety, panic and modification of lifestyle. The causative agents, members of the order Hymenoptera, are the honeybee, yellow jacket, hornet, and wasp. In addition, the fire ant which is a non-winged Hymenoptera, is responsible for numerous reactions in the Southeastern United States and along the Gulf Coast (2). The major advances which have occurred in recent years in understanding of insect sting allergy have occurred primarily because of two factors; the availability of purified insect venoms for diagnosis and treatment and the development of methodology for measurement of immunologic markers, serum venom specific IgE, the immunologic mediator of allergy and serum venom specific IgG, the immunologic mediator of immunity. The clinical applications of measurement of these immunologic parameters have resolved the majority of the diagnostic and therapeutic issues. In addition, there are numerous analogies which have application to other immediate hypersensitivity reactions such as allergic rhinitis (hay fever), food allergy and drug allergy.
From the Division of Allergy and Immunology, Departments of Medicine and Pediatrics, State University of New York at Buffalo, Buffalo, New York. 7
8
ROBERT E. REISMAN
INSECT STING REACTIONS The usual or normal reaction following an insect sting is local pain, erythema and swelling. In contrast to insect bites, insect stings always cause pain. This normal reaction usually subsides in 1 to 2 hours and does not require treatment other than local applications of cold compresses and analgesics. More extensive local reactions may occur following an insect sting, with swelling extending from the sting site over a large area, often peaking at 48 hours and lasting as along as 1 week. If severe, this reaction is sometimes accompanied by fatigue and nausea. The usual medical treatment for large local reactions is aspirin and antihistamines. If the reaction is extensive and disabling, steroids, such as prednisone, 40 mg daily for 2 to 3 days, are very helpful in reducing the local swelling. The most serious reaction is insect sting anaphylaxis. This reaction affects approximately 0.4% of the population. These reactions can occur at any age. Most have occurred in individuals under the age of 20 years, with a male-to-female ratio of 2:1. In all likelihood, the incidence is a reflection of exposure rather than of any specific age or sex predilection. Approximately one third of individuals who have had systemic reactions from insect stings have a personal history of atopic disease. Reactions may occur from stings on any area of the body (3, 4, 5). The clinical symptoms of anaphylaxis vary from patient to patient and are typical of anaphylaxis from any cause. The most common symptoms are dermal: generalized urticaria, flushing and angioedema. More serious symptoms are respiratory and cardiovascular. Upper airway edema involving the pharynx and epiglottis and circulatory collapse with shock and hypotension have been responsible for fatalities. Other less common symptoms include diarrhea and uterine contractions. In most patients these symptoms occur within 15 to 20 minutes after a sting, although, occasionally, reactions can occur as long as 72 hours after the sting. Clinical observations suggest that the sooner the symptoms occur, the more severe the reaction. Severe anaphylaxis can occur in all age groups. Most deaths due to insect sting anaphylaxis occur in adults. The presence of cardiovascular disease or other pathologic changes associated with age may be responsible for the increased incidence of fatalities in adults, who may have less tolerance for the fairly significant biochemical and physiologic changes that accompany anaphylaxis. Most patients who have severe anaphylactic reactions have no warning of their sensitivity. As a rule, prior stings have been tolerated with no or little difficulty. The use of beta adrenergic antagonists is associated with more severe reactions.
INSECT STING ALLERGY
9
Diagnosis The diagnosis of insect sting allergy is confirmed by the positive immediate skin test reaction, a wheal and flare reaction which occurs 10-15 minutes after a puncture or intradermal test with diluted insect venoms. Individual honeybee, yellow jacket, yellow hornet, bald faced hornet and wasp venoms are available for the diagnosis and treatment of insect sting allergy. Current recommendations are to skin test individuals with relevant histories with appropriate dilutions of each of the available Hymenoptera venom preparations. An immunologically specific reaction is elicited by venom concentrations equal to or less than 0.1 mcg per ml to 1.0 mcg per ml. Measurement of serum venom specific IgE by the radioallergosorbent test (RAST) also can be done but this test is not as sensitive as the skin test and may be negative in as many as 20% of individuals who are skin test positive. Natural History In recent years, much has been learned about the natural history of insect sting allergy (6). Patients have been observed who: (1) had a history of anaphylaxis after an insect sting, (2) had venom specific IgE documented by positive skin tests or in the serum by the RAST at the time of evaluation, (3) did not receive venom immunotherapy (discussed below) and (4) had a subsequent insect sting. The results of these studies may be summarized as follows: (1) Overall in an unselected population approximately 60% of individuals with prior allergic sting reactions have re-sting allergic reactions. (2) The re-sting reactions are more likely to occur in adults than in children. (3) The occurrence of more severe anaphylactic symptoms, such as shock, hypotension and loss of consciousness, is a high risk factor for repeat sting reactions. (4) Insect sting allergy is a relatively benign process and self limiting for children with urticaria as the only allergic symptom and may be benign for adults with similar mild reactions. Similar analogies to the self limiting nature of the clinical disease and the dichotomy between the continued presence of IgE antibody as detected by a positive skin test and the lack of clinical symptoms, also have been observed in patients with hay fever, food allergy, and drug allergy. It is not unusual for patients who no longer have clinical symptoms of ragweed hay fever, to retain their positive skin test reaction for many years. Children with certain food allergies such as egg and milk retain their positive skin tests, but lose clinical sensitivity as they grow older. There have been reports of a few patients who tolerate penicillin in the presence of positive skin tests. In this situation, if the drug is necessary, it is usually administered in a desensitization protocol.
10
ROBERT E. REISMAN
Therapy Individuals with a history of an acute allergic reaction following an insect sting and positive venom skin tests are considered at risk for subsequent sting reactions. Therapeutic recommendations include measures to minimize exposure to insects, the availability of emergency medication for medical treatment of anaphylaxis (epinephrine) and venom immunotherapy. As noted above, children who have had dermal symptoms only, have a benign prognosis and do not require venom immunotherapy. The documentation that adults with a similar reaction have a similar benign prognosis has not been as well substantiated. All patients who have had severe symptoms of anaphylaxis and have positive venom skin tests should receive venom immunotherapy regardless of the interval since the last sting reaction. These criteria are summarized in Table I. The details of venom immunotherapy have been reasonably defined in recent years and are outlined on Table II. The selection of venom is based upon knowledge of the culprit insect and the skin test reaction. When the identity of the culprit insect is not known and there are multiple positive skin test reactions, which is not an uncommon problem because of cross sensitivity between venoms, it may be necessary to administer multiple venoms. As a rule venom immunotherapy is initiated at doses of 0.1 to 1 mcg and gradually increased to a top maintenance dose ranging between 50 to 100 mcg. Therapy is then continued once monthly and the interval extended to six or eight weeks after the first or second year. The results of venom immunotherapy are almost 100% TABLE 1 Indications for Venom Immunotherapy in the Presence of Positive Skin Tests* Venom
Reaction
Immunotherapy
No Normal-transient pain, swelling No Large Local Anaphylaxis-severe Yes Children Yes Adults Anaphylaxis-dermal reaction only No Children Yes-under review Adults Yes Toxic** * Venom immunotherapy is not indicated in individuals with negative venom skin tests. ** Toxic reactions are due to multiple stings. The symptoms mimic symptoms of anaphylaxis. Patients may become sensitized and are then at risk for anaphylaxis from subsequent single stings.
11
INSECT STING ALLERGY TABLE 2 Details of Venom Immunotherapy Individual venom whenever possible Venom Selection based upon history and skin test reactivity 0.1 to 1.0 mcg Initial Dose 50 mcg Top Dose 4 weeks; extend to 6-8 weeks after 1 year Maintenance Interval Duration of Therapy a) 3 to 5 years; depends upon nature of anaphylaxis or
b) Negative skin test reaction
effective (7, 8). A number of studies have shown a very low re-sting reaction rate in treated patients. Successful venom immunotherapy is associated with the development of venom specific IgG, although the absolute titers of these antibodies do not appear to be a critical indicator of immunity. Criteria for the duration of venom immunotherapy are still evolving. Suggested criteria include the conversion to a negative skin test (9), the fall in serum IgE antibody titer to insignificant levels (10) and a finite period of time three to five years (11, 12, 13, 14). From a practical viewpoint it would appear that three years of therapy is sufficient for patients who have had mild to moderate symptoms of anaphylaxis. Patients who have had severe anaphylaxis may require longer periods of therapy to assure continued protection. The immunologic responses to venom immunotherapy are similar to those found after treatment with other types of allergenic extracts. IgG antibodies appear to play a protective role in successful desensitization of patients with drug allergies, such as penicillin. It is more difficult to assess the role of these antibodies in classic treatment of inhalant allergy, (rhinitis, asthma) but in general elevated titers are associated with improved clinical responses. Insect sting allergy reflects many of the typical clinical and immunologic features of other types of immediate hypersensitivity reactions. Unresolved issues persist such as factors influencing the development of insect sting allergy and the persistence of immunologic reactivity (IgE antibody) in the absence of clinical sensitivity. REFERENCES 1. Barnard JH: Studies of 400 Hymenoptera sting deaths in the United States. J Allergy Clin Immunol 1973; 52: 259 2. Stafford CT, Hoffman DR, Rhoades RB: Allergy to imported fire ants. South Med J 1989; 82: 152
12
ROBERT E. REISMAN
3. Brown H, Bernton HS: Allergy to Hymenoptera. Arch Inter Med 1970; 125: 665 4. Frazier CA: Allergic reactions to insect stings: A review of 180 cases. South Med J 1964; 57: 1028 5. Mueller HL, Schmid WH, Rubinsztain R: Stinging insect hypersensitivity: A 20 year study of immunologic treatment. Pediatrics 1975: 55: 530 6. Reisman RE: Natural history of insect sting allergy: Relationship of severity of symptoms of initial sting anaphylaxis to re-sting reactions. J Allergy Clin Immunol 1992; 90: 335 7. Valentine MD: Insect venom allergy: Diagnosis and treatment. J Allergy Clin Immunol 1984; 73: 299 8. Reisman RE, Livingston A. Venom immunotherapy: Ten years of experience with administration of single venoms and 50 jtg maintenance doses. J Allergy Clin Immunol 1992; 89: 1189 9. Golden DBK, Johnson K, Addison BI, et al: Clinical and immunologic observations in patients who stop venom immunotherapy. J Allergy Clin Immunol 1986; 77: 435 10. Reisman RE, Lantner R: Further observations on discontinuation of venom immunotherapy: Comparisons of patients stopped because of a fall in serum venom-specific IgE to insignificant levels with patients stopped "prematurely" by self choice. J Allergy Clin Immunol 1989; 83: 1049 11. Golden DBK, Kwiterovich KA, Kagey-Sobotka A, et al: Discontinuing venom immunotherapy (VIT): Determinates of clinical reactivity [abstract]. JAllergy Clin Immunol 1988; 81: 262 12. Schuberth KC, Kwiterovich KA, Kagey-Sobotka A, et al: Starting and stopping venom immunotherapy (VIT) in children with insect sting allergy [abstract]. J Allergy Clin Immunol 1988; 81: 200 13. Mueller U, Berthold E, Helbling A: Honey bee venom allergy: Results of a sting challenge one year after cessation of successful venom immunotherapy in 86 patients. J Allergy Clin Immunol 1991; 87: 702 14. Hauggard L, Norregaard OFH, Dahl R: In-hospital sting challenge in insect venom allergic patients after discontinuation of venom immunotherapy. J Allergy Clin Immunol 1991; 87: 699
DISCUSSION Middleton, Buffalo: A question occurred to me this morning that I don't think I've ever asked you before and that is, is anything known about the role of the eosinophil in this type of Hymenoptera sensitivity. I wondered if the neurologic symptoms could be related to the eosinophil-derived neurotoxin and the so-called Gordon phenomenon. Reply: The eosinophil is not involved. As I indicated, the majority of patients who have sting reaction are non-atopic, and they don't have hay fever or asthma, and would not be expected to have eosinophils. I don't think anybody understands the nature of the neurologic reactions that rarely occur after insect stings. We have studied two people who did have antimyelin antibodies. Not knowing what the Gordon phenomena is, I'm sorry I can't
answer that further. Douglas, Princeton: I have two practical questions. One is, you discussed active immunization, which seems to be very effective. Is there any information on passive immunization with specific IgG antibodies, for instance, in a child who is severely allergic so he or she can get some protection early? Secondly, in the longer term, do you have any idea what is going to happen five or 10 years after stopping immunotherapy? Do you need booster injections? Is there a possibility that as the IgG antibodies fall, that IgE will rebound? Is there any information on that?
INSECT STING ALLERGY
13
Reisman: Obviously, that information is accruing. If one looks back to the old days of treatment of this disease with an ineffective antigen and realizes we were looking at the natural history of the disease, it is clear that patients lost their allergy. That is, individuals who have had reactions in childhood, and never were treated effectively, may not react to insect stings as adults. So I think it is a self-limiting disease for many people. To date, from our studies that go back 15 years, we have not seen a return of allergy in the majority of individuals who stopped treatment. Have you studied the antibody profile of those individuals? Reisman: IgE and IgG tend to fall off. That is, if you are not exposed to venom, the antibodies tend to decrease. The IgG falls off very quickly, and that is one of the problems after stopping treatment. IgE antibodies, as you know, can persist for a long period of time, fall off more slowly and eventually, disappear. Of course, there are people who retain some degree of IgE antibodies and still don't react to stings for reasons not really understood. This dichotomy between immunologic and clinical reactivity remains a major problem. Your other question concerned passive immunization. That's a very interesting question. Hyperimmune gamma globulin can be obtained from bee keepers. Bee keepers, as I indicated earlier, are very immune. They have high levels of IgG because they are stung repeatedly. If you passively administer this IgG antibody, people are protected for a short period of time, roughly about three weeks. The original studies were done by Lessof and Lichtenstein in England. They showed that passive administration of IgG did protect allergic individuals against reactions from venom exposure. There had been attempts to utilize passive immunization to protect patients immediately while initiating active immunization and in individuals who had reactions to venom immunization. Venom immunization involves giving gradually increasing doses of venom until you reach an adequate maintenance protection dose. There are some patients who react to exquisitely small venom doses. Passively administered IgG might prevent some of these reactions and allow active immunization to proceed. Fortunately, this approach is rarely required. Odell, Salt Lake City: This is also a practical question. Do you use a specific venom from the species of bee that the individual is allergic to, or a mixture of venom from all bees? Reisman: We try very hard to use venom of a specific species. We test, as a rule, with the commercial venoms, which are hornet, yellow jacket, wasp, and honeybee. One of the problems is that there is extensive cross reaction, particularly among the vespids, yellow jacket, hornet and wasp. As much as possible, based on history and knowledge of the culprit stinging insect, we try to individualize venom therapy. When this is impossible, it may be necessary to administer multiple venoms. Horwitz, Philadelphia: I'm very interested in this, both from the point of view of a physician and also as a patient. I've been using prednisone, or steroids, and that has made a great deal of difference in my life as far as this is concerned. I got advice about these long term immunizations and I just decided that I'd wait until I got stung and then take some prednisone. I had no trouble at all. You didn't mention anything about the steroids. Do you use them at all? Reisman: Time didn't allow me to discuss every aspect of insect sting allergy. Individuals at risk of a severe sting reaction are taught to administer epinephrine. Epinephrine is the drug of choice for any severe anaphylactic reaction. It comes in pre-packaged syringes and in a more convenient form, marketed as Epi Pen. The drug of choice for an immediate allergic reaction is epinephrine, which is given along with antihistamines. Prednisone is not effective for an immediate allergic reaction. It is effective for treatment of large local reactions, such as serum sickness reaction. McCarty, Milwaukee: My question was the same as Dr. Horwitz's. Whether a little pop of epinephrine at the time of the bite might be more cost effective?
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ROBERT E. REISMAN
Reisman: The difference is that we can almost guarantee someone full immunity by giving them venom injections. Epinephrine should ameliorate the reaction, but there still have been very severe reactions in people taking epinephrine. Secondly, if you ever talked to people for whom you have prescribed epinephrine, after the first few months, they usually don't carry it with them all the time. You never know when a sting is going to occur.
