Symposium on Pediatric Allergy
Stinging Insect Allergy Current Concepts and Problems
Robert E. Reisman, M.D.,* and Carl E. Arbesman, M.D. t
Allergic reactions due to stinging insects (bee, wasp, yellow jacket, hornet) account for approximately 40 documented deaths per year in this country,t with the probability that further mortalities go unrecognized. Precise data concerning morbidity are not available but certainly acute allergic reactions are prevalent every summer. Important information regarding the pathogenesis of allergy and immunity to stinging insects has been developed in recent years. The ramifications of this knowledge may change traditional concepts of diagnosis and treatment of stinging insect allergy and may have important implications relating to other types of allergic reactions. The purpose of this article is to review some of the various problems current in this field, presenting data from animal and human studies. This presentation will not be concerned with the fairly classical concepts of insect avoidance and availability of emergency medication for subjects at risk. Types of Reactions to Stinging Insects A classification of reactions due to stinging insects is shown in Table 1. Mild local reactions refer to the usual reactions encountered following an insect sting. Usually the sting site is swollen, painful, and erythematous for several hours. Moderate to severe local reactions refer to swelling which extends from the sting site and may last several days. For example, swelling from a sting on the finger may extend to the wrist or elbow. The pathogenesis of such reactions is not clear, but this type of reaction has been known to precede subsequent systemic reactions. From the Allergy Research Laboratory of the Buffalo General Hospital and the Departments of Medicine and Microbiology of the State University of New York at Buffalo. *Clinical Associate Professor of Medicine tClinical Professor of Medicine and Professor of Microbiology This study was supported in part by United States Public Health Service research grant 5R01-AI-01303, and Allergic Disease Clinical Centers grant 2-P15-AI-10404 of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Pediatric Clinics of North America- Vol. 22, No. 1, February 1975
185
-----------------------------------------------
186
ROBERT
Table 1.
E.
REISMAN AND CARL
E.
ARBESMAN
Reactions Due to Stinging Insects None Local-mild Local-moderate to severe Generalized- immediate Generalized-delayed (vascular) Toxic
Scattered reports can be found of reactions occurring several days following an insect sting and usually involving small blood vessels and resulting in vasculitis or neuritis. The pathogenesis of this type of reaction is not known. Systemic reactions following insect stings are fairly classical of any type of any anaphylactic reaction. Usually the reaction begins within a few minutes following a sting but reportedly has started as much as 24 hours later. Classical symptoms which occur may involve the skin with urticaria and angioedema; the upper respiratory tract with edema and swelling of the larynx, particularly; the lower respiratory tract with asthma; the gastrointestinal tract with diarrhea and vomiting; and the circulatory system with resultant hypotension, shock, and death. Toxic reactions refer to those induced by multiple stings. Venom contains numerous pharmacologically active agents, and in enough quantity these agents are capable of causing systemic symptoms (Table 2). Finally, the word "none" heads the list of reactions in Table 1. There are individuals, particularly bee keepers, who experience practically no reaction following a sting. Such individuals are for practical purposes immune and probably represent the antithesis of the allergic individual. Current Problems of Pathogenesis and Therapy DIAGNOSIS. As acute systemic reactions from stinging insects occur immediately and have the cardinal signs and symptoms of a typical anaphylactic reaction, an lgE immunopathogenesis is certainly likely. Skin testing with currently available whole body insect extracts has not been reliable. 7 A substantial number of positive reactions have occurred in nonallergic individuals and it has been estimated that about 25 per cent of individuals who suffered acute systemic allergic reactions have negative skin tests. Among the proposed answers to this problem are: A. Inappropriate testing antigen. It is presumed that individuals sensitive to stinging insects are reacting to venom, the material which is actually introduced into the skin. Animal work has confirmed the presence of a tissue specific antigen in venom. 8 The possibilities exist that such an antigen is present in too small quantities in whole body extract to provide a reliable diagnostic test.
Table 2. Histamine Phospholipase A Phospholipase B Melli tin
Contents of Bee Venom Apamine Lecithinase Hyaluronidase Vany! mandelic acid
STINGING INSECT ALLERGY
187
B. Some reactions from stinging insects may be on a nonreaginic basis. It is possible that there are other immunologic mediators or, perhaps, reactions due to the pharmacologically active agents in venom with no antibody involvement. THERAPY. The time-honored accepted therapy for individuals at risk includes the use of hyposensitization (immunotherapy) with currently available whole body insect extracts. Numerous clinical reports attest to the efficacy of this form of treatment. The largest study was conducted by the Insect Committee of the American Academy of Allergy.3 In the group of patients receiving immunotherapy, over 95 per cent of those re-stung had less difficulty. This was compared to a group of nonimmunized patients, in which approximately 60 per cent of patients had less difficulty after re-sting. While these data impressively support the therapeutic value of whole body extracts, the improvement in the nontreated group is difficult to explain. Furthermore, treatment failures with whole body extract have been reported,9 and at least in two instances pure venom proved subsequently to be therapeutically effective.2· 5 The problems of evaluation of therapeutic agents have been further compounded by the species specificity of different venoms. Patients may clearly be sensitive to one insect and not another.6 Thus re-sting experience may be misinterpreted, unless insect identification is precise. Recent immunologic studies have suggested that as compared to whole venom, whole body extracts are poor antigens in humans with little stimulation of blocking type IgG antibody.10 These observations have thus put the therapeutic efficacy of whole body extracts in some doubt.
Animal Studies Rabbits immunized with whole body insect extracts and insect venoms develop quite specific precipitating antibodies. An example of one gel precipitation experiment showing the reaction occurring between bee venom and its antisera and whole body bee extract and its antisera is depicted on Figure 1. There is no cross sensitivity between venom and whole body extracts, i.e., bee venom does not react with bee body antisera and bee body extract fails to react to bee venom antisera.
Figure 1. Gel precipitation experiment showing :reactions between bee venom (BV) and bee body extracts B 0 B and BLB) and respective rabbit antisera (aBV and aBB). Bee venom antisera reacts only with bee venom and not with whole body bee extracts. Similarly, whole bee body antisera reacts only with its homologous antigen and not with bee venom.
188
ROBERT
Table 3.
E.
REISMAN AND CARL
E.
ARBESMAN
Reaction of Anti-Bee Venom Mouse Sera with Insect Venoms and Extracts 48
HOUR PCA
Bee venom Yellow jacket venom Bee-whole body Yellow jacket-whole body Wasp-whole body Hornet-whole body
+
2 HOUR PCA
PRECIPITATING ANTIBODY
+
+
Reactions in yellow jacket system were quite similar. These data suggested that the rabbit recognizes pure venom and whole body extracts as dissimilar. Further studies using the very sensitive hemagglutination inhibition technique confirmed these findings. Bee and yellow jacket venoms were also found to contain species-specific antigens, reacting with their homologous antisera only. In order to study these relationships in a model more akin to the human, reaginic type antibodies were raised in mice4 and examined by the 48 hour passive cutaneous anaphylaxis (PCA) method. Two hour PCA, 48 hour PCA, and precipitating antibodies reacting with bee venom were all detected. These antibodies failed to react to any of the whole body extracts or to yellow jacket venom (Table 3). Human Studies- Detection of Venom-Specific IgE Antibodies The radioallergosorbent test (RAST) was adapted for measurement of lgE specific antibodies." Cellulose particles were coated with venoms obtained from bees, yellow jackets, and bald face hornets. This technique proved to be reliable for detection of lgE venom specific antibodies and very reproducible. RAST results were expressed as a percentage of standard serum that had a radioactive count of approximately 21f2 times that of control norma! serum. In the case of bee venom this standard had a passive transfer titer of 100. RAST levels greater than 25 per cent were considered significant. RELATIONSHIP OF VENOM ANTIBODIES MEASURED BY RAST TO RESULTS OF WHOLE BoDY ExTRACT SKIN TESTS. Skin test data using whole body bee extracts were available in 47 patients. Considering areaction to a 1:10,000 dilution (.01 per cent) of this extract as significant, the majority of patients with elevated bee venom RAST levels had positive tests. However, there were also 22 patients with bee venom RAST levels below 25 per cent who had similar positive skin tests. Thus, these results confirm the poor reliability of skin tests with whole body bee extracts. INCIDENCE OF IGE ANTIBODIES. Patients with Systemic Reactions: Sera of 109 patients who had systemic reactions following insect stings were analyzed. These results are found in Table 4. Significant antibodies (RAST greater than 25 per cent) reacting with bee venom were
189
STINGING INSECT ALLERGY
Table 4.
Summary of Incidence of IgE Venom Antibodies in Sera of Systemic Reactors VENOMS
Bee
Yellow Jacket
IgE antibodies RAST >25 per cent 46 No IgE antibodies RAST 1000 ''Numbers in larger type indicate sera reacting with one venom only.
parison of bee and bald face hornet venoms and bald face hornet and yellow jacket venoms. These studies clearly show that patients may be sensitive to one of two venoms and not react to other insects. Recognition of this factor is most important in any attempt to evaluate or analyze current problems such as the role of immunotherapy and the effects of repeated stings.
Effect of Sting on IgE Antibodies Following a sting, patients with allergic reactions develop a rising titer of IgE antibodies, reaching a maximum response in approximately
Table 6.
Effect of Sting upon IgE Antibody IGE
UNITS PER ML
Pt
Pt
RAST
Bee
PER CENT STD.
Yellow Jacket
Hornet
WP Day 3 Day 17
200 3600
3 5
24 850
10 119
Day4 Day 18
97 63
178 422
25 28
6 8
DA
191
STINGING INSECT ALLERGY
Table 7.
Effect of Therapy (?) with Whole Body Extract BEE VENOM RAST
YELLOW JACKET VENOM RAST
PerCentSTD
PerCentSTD
PT SM
PT CA 5/70 7/70 5/72 9/73
100 111 99 51
8/72 5/73 10/73
236 38 43
2 to 3 weeks. The response may also be quite specific for the offending insect venom. Two typical examples are shown on ·Table 6. The first patient, W. P., developed a typical immediate anaphylactic reaction following a yellow jacket sting. Serum taken on day 3 showed a border line yellow jacket venom RAST level of 24 per cent and no bee or hornet reaction. These results suggest that the sting may have effectively neutralized some of the previously available reagin. On day 17, 2 weeks later, the yellow jacket IgE antibody rose to 850 per cent. There was also some rise in the hornet reaction and no bee venom response occurred. It was also of interest that, in this patient, total IgE levels also rose. The second patient developed a fairly typical serum sickness reaction with urticaria and joint pain approximately 4 days after an insect sting. Serum taken at that time revealed an increased titer of bee venom antibody. Serum taken 2 weeks later, following full recovery, revealed that the IgE bee venom antibody had risen considerably. There was no response of yellow jacket and hornet antibody.
Effect of Therapy with Whole Body Extracts on IgE Antibody As of this date a number of patients have been followed during the course of specific injection therapy with currently available whole body extracts. In Table 7, venom RAST levels of two patients are shown. PatientS. M. was our original standard (100 per cent). Over a period of 3 years his bee venom IgE antibody has dropped to one half its original value. Patient C. A.'s yellow jacket IgE levels dropped considerably over a period of 1 year. The fundamental question yet to be ascertained is whether this fall in lgE antibody is a reflection of the specific injection treatment or other factors such as time alone. This question is certainly the crux of the present day controversy regarding efficacy of whole body extracts as an appropriate form of immunotherapy for individuals at risk. Further observations should provide the definitive answer.
REFERENCES L Barnard, J_ H.: Studies of 400 hymenoptera sting deaths in the United States. J. Allerg. Clin. Immun., 52:259-264, 1973. 2. Busse, W., Reed, C. E., Lichtenstein, L. W., and Reisman, R. E.: Protection following honeybee venom immunotherapy in a case of beesting anaphylaxis. J. All erg. Clin. Immun., 53:104, 1974.
192
RoBERT
E.
REISMAN AND CARL
E.
ARBESMAN
3. Insect Allergy Committee of the American Academy of Allergy: Insect sting allergy: questionnaire, study of 2606 cases. J.A.M.A., 193:115-120, 1965. 4. Levine, B. B., and Chang, H., Jr.: Effect of time interval between antigen injections on reagin and IgG, antibody titers in low dose immunization in mice. Int. Arch. Allerg., 40:113-116, 1971. 5. Lichtenstein, L. M., Valentine, M.D., and Sobotka, A. K.: A case for venom treatment in anaphylactic sensitivity to hymenoptera sting. N. Eng. J. Med., 290:1223-1227, 1974. 6. Reisman, R. E., Wypych, J. 1., Yeagle, N., and Arbesman, C. E.: Stinging insect hypersensitivity. III. Detection and clinical significance of lgE antibodies to insect venom in man. J, Allerg. Clin. Immun., 53:110-111, 1974. 7. Schwartz, H. L.: Skin sensitivity in insect allergy. J.A.M.A., 194:703-705, 1965. 8. Shulman, S., Bigelson, F., Lang, R., and Arbesman, C. E.: The allergic response to stinging insects: Biochemical and immunologic studies on bee venom and other bee body preparations. J, Immun., 96:29-38, 1966. 9. Torsney, P. J.: Treatment failure; insect desensitization. J. Allerg. Clin. Immun., 52:303306, 1973. 10. Valentine, M. D., Sobotka, A. K., and Lichtenstein, L. M.: Blocking antibody to bee venom: Induction by venom and not by whole body extracts. J. Allerg. Clin. lmmun., 53:105, 1974. 11. Wide, L., Bennich, H., and Johansson, S. G. 0.: Diagnosis of allergy by an in vitro test for allergen antibodies. Lancet, 2:1105-1107, 1967. Suite 1102 General Medical Towers 50 High Street Buffalo, New York 14203
Stinging Insect Allergy Current Concepts and Problems
Robert E. Reisman, M.D.,* and Carl E. Arbesman, M.D. t
Allergic reactions due to stinging insects (bee, wasp, yellow jacket, hornet) account for approximately 40 documented deaths per year in this country,t with the probability that further mortalities go unrecognized. Precise data concerning morbidity are not available but certainly acute allergic reactions are prevalent every summer. Important information regarding the pathogenesis of allergy and immunity to stinging insects has been developed in recent years. The ramifications of this knowledge may change traditional concepts of diagnosis and treatment of stinging insect allergy and may have important implications relating to other types of allergic reactions. The purpose of this article is to review some of the various problems current in this field, presenting data from animal and human studies. This presentation will not be concerned with the fairly classical concepts of insect avoidance and availability of emergency medication for subjects at risk. Types of Reactions to Stinging Insects A classification of reactions due to stinging insects is shown in Table 1. Mild local reactions refer to the usual reactions encountered following an insect sting. Usually the sting site is swollen, painful, and erythematous for several hours. Moderate to severe local reactions refer to swelling which extends from the sting site and may last several days. For example, swelling from a sting on the finger may extend to the wrist or elbow. The pathogenesis of such reactions is not clear, but this type of reaction has been known to precede subsequent systemic reactions. From the Allergy Research Laboratory of the Buffalo General Hospital and the Departments of Medicine and Microbiology of the State University of New York at Buffalo. *Clinical Associate Professor of Medicine tClinical Professor of Medicine and Professor of Microbiology This study was supported in part by United States Public Health Service research grant 5R01-AI-01303, and Allergic Disease Clinical Centers grant 2-P15-AI-10404 of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Pediatric Clinics of North America- Vol. 22, No. 1, February 1975
185
-----------------------------------------------
186
ROBERT
Table 1.
E.
REISMAN AND CARL
E.
ARBESMAN
Reactions Due to Stinging Insects None Local-mild Local-moderate to severe Generalized- immediate Generalized-delayed (vascular) Toxic
Scattered reports can be found of reactions occurring several days following an insect sting and usually involving small blood vessels and resulting in vasculitis or neuritis. The pathogenesis of this type of reaction is not known. Systemic reactions following insect stings are fairly classical of any type of any anaphylactic reaction. Usually the reaction begins within a few minutes following a sting but reportedly has started as much as 24 hours later. Classical symptoms which occur may involve the skin with urticaria and angioedema; the upper respiratory tract with edema and swelling of the larynx, particularly; the lower respiratory tract with asthma; the gastrointestinal tract with diarrhea and vomiting; and the circulatory system with resultant hypotension, shock, and death. Toxic reactions refer to those induced by multiple stings. Venom contains numerous pharmacologically active agents, and in enough quantity these agents are capable of causing systemic symptoms (Table 2). Finally, the word "none" heads the list of reactions in Table 1. There are individuals, particularly bee keepers, who experience practically no reaction following a sting. Such individuals are for practical purposes immune and probably represent the antithesis of the allergic individual. Current Problems of Pathogenesis and Therapy DIAGNOSIS. As acute systemic reactions from stinging insects occur immediately and have the cardinal signs and symptoms of a typical anaphylactic reaction, an lgE immunopathogenesis is certainly likely. Skin testing with currently available whole body insect extracts has not been reliable. 7 A substantial number of positive reactions have occurred in nonallergic individuals and it has been estimated that about 25 per cent of individuals who suffered acute systemic allergic reactions have negative skin tests. Among the proposed answers to this problem are: A. Inappropriate testing antigen. It is presumed that individuals sensitive to stinging insects are reacting to venom, the material which is actually introduced into the skin. Animal work has confirmed the presence of a tissue specific antigen in venom. 8 The possibilities exist that such an antigen is present in too small quantities in whole body extract to provide a reliable diagnostic test.
Table 2. Histamine Phospholipase A Phospholipase B Melli tin
Contents of Bee Venom Apamine Lecithinase Hyaluronidase Vany! mandelic acid
STINGING INSECT ALLERGY
187
B. Some reactions from stinging insects may be on a nonreaginic basis. It is possible that there are other immunologic mediators or, perhaps, reactions due to the pharmacologically active agents in venom with no antibody involvement. THERAPY. The time-honored accepted therapy for individuals at risk includes the use of hyposensitization (immunotherapy) with currently available whole body insect extracts. Numerous clinical reports attest to the efficacy of this form of treatment. The largest study was conducted by the Insect Committee of the American Academy of Allergy.3 In the group of patients receiving immunotherapy, over 95 per cent of those re-stung had less difficulty. This was compared to a group of nonimmunized patients, in which approximately 60 per cent of patients had less difficulty after re-sting. While these data impressively support the therapeutic value of whole body extracts, the improvement in the nontreated group is difficult to explain. Furthermore, treatment failures with whole body extract have been reported,9 and at least in two instances pure venom proved subsequently to be therapeutically effective.2· 5 The problems of evaluation of therapeutic agents have been further compounded by the species specificity of different venoms. Patients may clearly be sensitive to one insect and not another.6 Thus re-sting experience may be misinterpreted, unless insect identification is precise. Recent immunologic studies have suggested that as compared to whole venom, whole body extracts are poor antigens in humans with little stimulation of blocking type IgG antibody.10 These observations have thus put the therapeutic efficacy of whole body extracts in some doubt.
Animal Studies Rabbits immunized with whole body insect extracts and insect venoms develop quite specific precipitating antibodies. An example of one gel precipitation experiment showing the reaction occurring between bee venom and its antisera and whole body bee extract and its antisera is depicted on Figure 1. There is no cross sensitivity between venom and whole body extracts, i.e., bee venom does not react with bee body antisera and bee body extract fails to react to bee venom antisera.
Figure 1. Gel precipitation experiment showing :reactions between bee venom (BV) and bee body extracts B 0 B and BLB) and respective rabbit antisera (aBV and aBB). Bee venom antisera reacts only with bee venom and not with whole body bee extracts. Similarly, whole bee body antisera reacts only with its homologous antigen and not with bee venom.
188
ROBERT
Table 3.
E.
REISMAN AND CARL
E.
ARBESMAN
Reaction of Anti-Bee Venom Mouse Sera with Insect Venoms and Extracts 48
HOUR PCA
Bee venom Yellow jacket venom Bee-whole body Yellow jacket-whole body Wasp-whole body Hornet-whole body
+
2 HOUR PCA
PRECIPITATING ANTIBODY
+
+
Reactions in yellow jacket system were quite similar. These data suggested that the rabbit recognizes pure venom and whole body extracts as dissimilar. Further studies using the very sensitive hemagglutination inhibition technique confirmed these findings. Bee and yellow jacket venoms were also found to contain species-specific antigens, reacting with their homologous antisera only. In order to study these relationships in a model more akin to the human, reaginic type antibodies were raised in mice4 and examined by the 48 hour passive cutaneous anaphylaxis (PCA) method. Two hour PCA, 48 hour PCA, and precipitating antibodies reacting with bee venom were all detected. These antibodies failed to react to any of the whole body extracts or to yellow jacket venom (Table 3). Human Studies- Detection of Venom-Specific IgE Antibodies The radioallergosorbent test (RAST) was adapted for measurement of lgE specific antibodies." Cellulose particles were coated with venoms obtained from bees, yellow jackets, and bald face hornets. This technique proved to be reliable for detection of lgE venom specific antibodies and very reproducible. RAST results were expressed as a percentage of standard serum that had a radioactive count of approximately 21f2 times that of control norma! serum. In the case of bee venom this standard had a passive transfer titer of 100. RAST levels greater than 25 per cent were considered significant. RELATIONSHIP OF VENOM ANTIBODIES MEASURED BY RAST TO RESULTS OF WHOLE BoDY ExTRACT SKIN TESTS. Skin test data using whole body bee extracts were available in 47 patients. Considering areaction to a 1:10,000 dilution (.01 per cent) of this extract as significant, the majority of patients with elevated bee venom RAST levels had positive tests. However, there were also 22 patients with bee venom RAST levels below 25 per cent who had similar positive skin tests. Thus, these results confirm the poor reliability of skin tests with whole body bee extracts. INCIDENCE OF IGE ANTIBODIES. Patients with Systemic Reactions: Sera of 109 patients who had systemic reactions following insect stings were analyzed. These results are found in Table 4. Significant antibodies (RAST greater than 25 per cent) reacting with bee venom were
189
STINGING INSECT ALLERGY
Table 4.
Summary of Incidence of IgE Venom Antibodies in Sera of Systemic Reactors VENOMS
Bee
Yellow Jacket
IgE antibodies RAST >25 per cent 46 No IgE antibodies RAST 1000 ''Numbers in larger type indicate sera reacting with one venom only.
parison of bee and bald face hornet venoms and bald face hornet and yellow jacket venoms. These studies clearly show that patients may be sensitive to one of two venoms and not react to other insects. Recognition of this factor is most important in any attempt to evaluate or analyze current problems such as the role of immunotherapy and the effects of repeated stings.
Effect of Sting on IgE Antibodies Following a sting, patients with allergic reactions develop a rising titer of IgE antibodies, reaching a maximum response in approximately
Table 6.
Effect of Sting upon IgE Antibody IGE
UNITS PER ML
Pt
Pt
RAST
Bee
PER CENT STD.
Yellow Jacket
Hornet
WP Day 3 Day 17
200 3600
3 5
24 850
10 119
Day4 Day 18
97 63
178 422
25 28
6 8
DA
191
STINGING INSECT ALLERGY
Table 7.
Effect of Therapy (?) with Whole Body Extract BEE VENOM RAST
YELLOW JACKET VENOM RAST
PerCentSTD
PerCentSTD
PT SM
PT CA 5/70 7/70 5/72 9/73
100 111 99 51
8/72 5/73 10/73
236 38 43
2 to 3 weeks. The response may also be quite specific for the offending insect venom. Two typical examples are shown on ·Table 6. The first patient, W. P., developed a typical immediate anaphylactic reaction following a yellow jacket sting. Serum taken on day 3 showed a border line yellow jacket venom RAST level of 24 per cent and no bee or hornet reaction. These results suggest that the sting may have effectively neutralized some of the previously available reagin. On day 17, 2 weeks later, the yellow jacket IgE antibody rose to 850 per cent. There was also some rise in the hornet reaction and no bee venom response occurred. It was also of interest that, in this patient, total IgE levels also rose. The second patient developed a fairly typical serum sickness reaction with urticaria and joint pain approximately 4 days after an insect sting. Serum taken at that time revealed an increased titer of bee venom antibody. Serum taken 2 weeks later, following full recovery, revealed that the IgE bee venom antibody had risen considerably. There was no response of yellow jacket and hornet antibody.
Effect of Therapy with Whole Body Extracts on IgE Antibody As of this date a number of patients have been followed during the course of specific injection therapy with currently available whole body extracts. In Table 7, venom RAST levels of two patients are shown. PatientS. M. was our original standard (100 per cent). Over a period of 3 years his bee venom IgE antibody has dropped to one half its original value. Patient C. A.'s yellow jacket IgE levels dropped considerably over a period of 1 year. The fundamental question yet to be ascertained is whether this fall in lgE antibody is a reflection of the specific injection treatment or other factors such as time alone. This question is certainly the crux of the present day controversy regarding efficacy of whole body extracts as an appropriate form of immunotherapy for individuals at risk. Further observations should provide the definitive answer.
REFERENCES L Barnard, J_ H.: Studies of 400 hymenoptera sting deaths in the United States. J. Allerg. Clin. Immun., 52:259-264, 1973. 2. Busse, W., Reed, C. E., Lichtenstein, L. W., and Reisman, R. E.: Protection following honeybee venom immunotherapy in a case of beesting anaphylaxis. J. All erg. Clin. Immun., 53:104, 1974.
192
RoBERT
E.
REISMAN AND CARL
E.
ARBESMAN
3. Insect Allergy Committee of the American Academy of Allergy: Insect sting allergy: questionnaire, study of 2606 cases. J.A.M.A., 193:115-120, 1965. 4. Levine, B. B., and Chang, H., Jr.: Effect of time interval between antigen injections on reagin and IgG, antibody titers in low dose immunization in mice. Int. Arch. Allerg., 40:113-116, 1971. 5. Lichtenstein, L. M., Valentine, M.D., and Sobotka, A. K.: A case for venom treatment in anaphylactic sensitivity to hymenoptera sting. N. Eng. J. Med., 290:1223-1227, 1974. 6. Reisman, R. E., Wypych, J. 1., Yeagle, N., and Arbesman, C. E.: Stinging insect hypersensitivity. III. Detection and clinical significance of lgE antibodies to insect venom in man. J, Allerg. Clin. Immun., 53:110-111, 1974. 7. Schwartz, H. L.: Skin sensitivity in insect allergy. J.A.M.A., 194:703-705, 1965. 8. Shulman, S., Bigelson, F., Lang, R., and Arbesman, C. E.: The allergic response to stinging insects: Biochemical and immunologic studies on bee venom and other bee body preparations. J, Immun., 96:29-38, 1966. 9. Torsney, P. J.: Treatment failure; insect desensitization. J. Allerg. Clin. Immun., 52:303306, 1973. 10. Valentine, M. D., Sobotka, A. K., and Lichtenstein, L. M.: Blocking antibody to bee venom: Induction by venom and not by whole body extracts. J. Allerg. Clin. lmmun., 53:105, 1974. 11. Wide, L., Bennich, H., and Johansson, S. G. 0.: Diagnosis of allergy by an in vitro test for allergen antibodies. Lancet, 2:1105-1107, 1967. Suite 1102 General Medical Towers 50 High Street Buffalo, New York 14203
