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Diagnosis of insect hypersensitivity
THE JOURNAL OF
ALLElPGY AND
CLINfCAL
I-OBY NUMBER 4
VOLUME 60
Editorial Diagnosis
of insect hypersensitivity
Anne K. Sobotka, Ph.D. Baltimore,
Md
Forty-seven years ago an attempt was made to diagnose insect hypersensitivity; a beekeeper, exposed daily to body proteins (by inhalation) and to venom proteins (parenterally), was found to be skin test-positive to proteins from both sources.’ This result served to justify the widespread use of body protein extracts of the Hymenoptera for assessing sensitivity and for treatment. A few physicians, most notably Dr. Loveless, found this regimen illogical and insisted that reactions to stings were caused by injected venom proteins. She prepared venom extracts for skin and conjunctival testing and for treatment; treatment via direct stings was also advocated.** 3 This approach gained only sparse acceptance due, in part, to the lack of controlled studies coupled with the substantially greater ease in obtaining whole body extracts and the reported clinical success with these materials. While detailed analysis of diagnosis or treatment using insect venoms was not carried out, many immunochemical studies were undertaken comparing the protein and antigenic content of body extracts versus venoms. Several such reports concluded that common antigens existed among body and venom proteins; the use of whole body extracts was thus justified and the practice continued.4-6 Recently, renewed interest in allergic reactions to insect stings has occurred for several reasons. First, although several retrospective studies supported the idea that 80% or more of patients were protected by whole body extract injections, many treatment failures on this therapy occurred.7-g Second, several investigators reported the failure of whole body extract skin tests to discriminate between patients who reported adverse sting reactions and persons who expeReprint requests to: Anne K. Sobotka, Ph.D., The Good Samaritan Hospital, 5601 Loch Raven Blvd., Baltimore, Md. 21239.
rienced no unusual response following a sting.‘O, ‘I In fact, many allergists thought reactions to stings were “toxic” or idiosyncratic. To determine whether untoward sting reactions were a manifestation of immediate hypersensitivity, studies using an in vitro model of IgE-mediated anaphylaxis, histamine release from human basophils, were undertaken. Comparisons of the whole body extract versus several vemons (honeybee, yellow jacket, and hornets) as antigens showed the venoms to clearly define the history-allergic patients while whole body extract elicited responses from normals as we11.12Moreover, IgE antibodies to venom proteins but not to body parts were found in sera from allergic patients (not previously treated with whole body extracts). l3 These results led to the establishment, where possible, of the diagnosis of insect allergy by histamine release. The study of sensitivity to Polistes wasp venom by Findlay and co-workers, which appears on page 230 of this issue of the Journal, is an example of the use of the histamine release assay as a diagnostic tool. The authors show that extruded venom from Polistes wasps clearly distinguishes history-wasp allergic patients from both normals and from patients purportedly sensitive only to honeybees and yellow jackets. These results, although not previously reported with regard to this venom, are not unexpected. Two facets of the report, dealt with thoroughly by the authors, are quite pertinent when management of insect allergy is considered and should be underscored. One of these is the vast difference in distribution and density of the several genera of Hymenoptera. The majority of studies in the literature to date were conducted in Northeastern United States where the Polistes wasp is uncommon as compared to the yellow jacket and the honeybee. The reverse is true in South Central United Vol. 60, No. 4, pp. 213-214
214 Editorial
States where Polistes varieties are predominant and the yellow jacket is rare. Findlay and co-workers also considered the subspecies cross-reactivity of Polistes wasps. Others have shown no relationship between the honeybee, vespids (yellow jacket, yellow hornet, white-faced hornet), or Polistes, whereas minor antigenic similarities occur among vespid venoms.14* l5 Over seventeen subspecies of Polistes have been reported, which is potentially a formidable problem. The authors, however, found almost total allergenic similarity between the venoms of the three Polistes subspecies tested. If this holds true for the other Hymenoptera species, collection of venom for diagnosis and therapy will be greatly simplified. Verification of their data by skin testing with the venoms from several Hymenoptera would have added strength to the article since such tests have been shown to be an excellent diagnostic tool in insect allergy.16* l7 Basophil histamine release is not an infallible test; approximately 15% of patients positive by skin test to one or more venoms have basophils that cannot be triggered to release histamine by an immune stimulus (antigen or anti-IgE) . l* Skin testing was not possible for the authors nor is it available as yet to physicians faced with frightened patients in need of an answer. This is a very serious problem. Most clinicians do not have the facilities to perform diagnostic histamine release or RAST assays whereas skin testing is routine. The evidence against the diagnostic utility of whole body extract skin tests leaves the practitioner in an untenable situation which will be improved only as preparations of venoms are made available. The necessity for definitive skin testing is twofold: (1) the patients potentially at risk will be defined and the causitive insect(s) known; (2) if the results in a similar syndrome, penicillin hypersensitivity, can be extended to insect allergy, then negative skin tests will be equally informative. In penicillin allergy, less than 1% of history-positive, skin test-negative patients experience systemic symptoms when re-exposed to the drug.is* 2oIn our experience over 50% of patients with a clear history of a systemic reaction have negative venom skin tests due to the decrease in IgE antibody with time. A large number of patients would thus be relieved of their fear of being stung and would not begin extended and perhaps unnecessary therapy. Under the auspices of the National Institute of Allergy and Infectious Diseases, venom solutions for skin testing have been prepared for distribution to Allergic Disease Centers throughout the United States. Once this plan is effected, diagnostic skin test capability will be available in large sections of this country, easing the problem to some extent. Until
J. ALLERGY
CLIN. IMMUNOL. OCTOBER 1977
standardized test solutions are within the reach of all practicing allergists, however, the application of extensive basic and clinical research efforts to improve patient care will not be possible. REFERENCES 1. Benson, R. L., and Semenov, H.: Allergy in its relation to bee sting, J. ALLERGY 1:105, 1930. 2. Loveless, M. H., and Fackler, W. R.: Wasp venom allergy and immunity, Ann. Allergy 14:347, 1956. 3. Loveless, M. H.: Immunization in wasp-sting allergy through venom repositories and periodic stings, J. Immunol. 89:204, 1962. 4. Foubert, E. L., Jr., and Steir, R. A.: Antigenic relationships between honeybees, wasps, yellow hornets, black hornets and yellow jackets, J. ALLERGY 29~13, 1958. 5. O’Connor, R., and Erickson, R.: Hymenoptera antigens: An immunological comparison of venoms, venom sac extracts and whole insect extract, Ann. Allergy 23: 151, 1965. 6. Shulman, S., Bigelsen, F., and Lang, R.: The allergic response to stinging insects: Biochemical and immunologic studies on bee venom and other bee body preparations, J. Immunol. 9629, 1966. 7. insect Allergy Committee of the American Academy of Allergy. Insect sting allergy: Questionaire study of 2,606 cases, J. A. M. A. 193:109, 1965. 8. Ordman, D.: Desensitization against the effects of bee stings, Int. Arch. Allergy Appl. Immunol. 28:366, 1965. 9. Torsney, P. J.: Treatment failure: Insect desensitization, J. ALLERGY CLIN. IMMUNOL. 52~303, 1973. 10. Schwartz, H.: Skin sensitivity in insect allergy, J. A. M. A. 194~703,1965. 11. Bernton, H. S., and Brown, H.: Studies on the Hymenoptera. I. Skin reactions of normal persons to honeybee (Apis nell. fera) extract, J. ALLERGY 36~315, 1966. 12. Sobotka, A. K., Valentine, M. D., Benton, A., and Lichtenstein, L. M.: Allergy to insect stings. I. The diagnosis of IgEmediated Hymenoptera sensitivity by venom-induced histamine release, J. ALLERGY CLIN. IMMUNOL. 53:170, 1974. 13. Hunt, K. J., Yunginger, J., Valentine, M. D., Sobotka, A. K., and Lichtenstein, L. M.: Sensitization as a result of Hymenoptera whole body extract treatment, J. ALLERGY CLIN. IMMUNOL. (Submitted for publication.) 14. Kern, F., Sobotka, A. K., Valentine, M. D., Benton, A., and Lichtenstein, L. M.: Allergy to insect stings. Ill. Allergenic cross-reactivity among the vespid venoms, J. ALLERGY CLIN. IMMUNOL. 57~554, 1976. 15. King, T. P.: Personal communication. 16. Hunt, K. J., Valentine, M. D., Sobotka, A. K., and Lichtenstein, L. M.: Diagnosis of allergy to stinging insects by skin testing with Hymenoptera venoms, Ann. Intern. Med. 85:56, 1976. 17. Zelesnick, L. D., Hunt, K. J., Sobotka, A. K., Valentine, M. D., Trippett, L. O., and Lichtenstein, L. M.: Diagnosis of Hymenoptera hypersensitivity by skin testing with Hymenoptera venoms, J. ALLERGY CLIN. IMMUNOL. 59~2, 1977. 18. Conroy, M. C., Adkinson, N. F., Jr., Sobotka, A. K., and Lichtenstein, L. M.: “Releasability” of histamine from human basophils, Fed. Proc. 36:1216, 1977. 19. Levine, B. B., and Zolov, D. M.: Prediction of penicillin allergy by immunological tests, J. ALLERGY 43:231, 1969. 20. Adkinson, N. F., Jr., Thompson, W. L., Maddrey, W. C., and Lichtenstein, L. M.: Routine use of penicillin skin testing on an inpatient service, N. Engl. J. Med. 285:22, 1971.
ALLElPGY AND
CLINfCAL
I-OBY NUMBER 4
VOLUME 60
Editorial Diagnosis
of insect hypersensitivity
Anne K. Sobotka, Ph.D. Baltimore,
Md
Forty-seven years ago an attempt was made to diagnose insect hypersensitivity; a beekeeper, exposed daily to body proteins (by inhalation) and to venom proteins (parenterally), was found to be skin test-positive to proteins from both sources.’ This result served to justify the widespread use of body protein extracts of the Hymenoptera for assessing sensitivity and for treatment. A few physicians, most notably Dr. Loveless, found this regimen illogical and insisted that reactions to stings were caused by injected venom proteins. She prepared venom extracts for skin and conjunctival testing and for treatment; treatment via direct stings was also advocated.** 3 This approach gained only sparse acceptance due, in part, to the lack of controlled studies coupled with the substantially greater ease in obtaining whole body extracts and the reported clinical success with these materials. While detailed analysis of diagnosis or treatment using insect venoms was not carried out, many immunochemical studies were undertaken comparing the protein and antigenic content of body extracts versus venoms. Several such reports concluded that common antigens existed among body and venom proteins; the use of whole body extracts was thus justified and the practice continued.4-6 Recently, renewed interest in allergic reactions to insect stings has occurred for several reasons. First, although several retrospective studies supported the idea that 80% or more of patients were protected by whole body extract injections, many treatment failures on this therapy occurred.7-g Second, several investigators reported the failure of whole body extract skin tests to discriminate between patients who reported adverse sting reactions and persons who expeReprint requests to: Anne K. Sobotka, Ph.D., The Good Samaritan Hospital, 5601 Loch Raven Blvd., Baltimore, Md. 21239.
rienced no unusual response following a sting.‘O, ‘I In fact, many allergists thought reactions to stings were “toxic” or idiosyncratic. To determine whether untoward sting reactions were a manifestation of immediate hypersensitivity, studies using an in vitro model of IgE-mediated anaphylaxis, histamine release from human basophils, were undertaken. Comparisons of the whole body extract versus several vemons (honeybee, yellow jacket, and hornets) as antigens showed the venoms to clearly define the history-allergic patients while whole body extract elicited responses from normals as we11.12Moreover, IgE antibodies to venom proteins but not to body parts were found in sera from allergic patients (not previously treated with whole body extracts). l3 These results led to the establishment, where possible, of the diagnosis of insect allergy by histamine release. The study of sensitivity to Polistes wasp venom by Findlay and co-workers, which appears on page 230 of this issue of the Journal, is an example of the use of the histamine release assay as a diagnostic tool. The authors show that extruded venom from Polistes wasps clearly distinguishes history-wasp allergic patients from both normals and from patients purportedly sensitive only to honeybees and yellow jackets. These results, although not previously reported with regard to this venom, are not unexpected. Two facets of the report, dealt with thoroughly by the authors, are quite pertinent when management of insect allergy is considered and should be underscored. One of these is the vast difference in distribution and density of the several genera of Hymenoptera. The majority of studies in the literature to date were conducted in Northeastern United States where the Polistes wasp is uncommon as compared to the yellow jacket and the honeybee. The reverse is true in South Central United Vol. 60, No. 4, pp. 213-214
214 Editorial
States where Polistes varieties are predominant and the yellow jacket is rare. Findlay and co-workers also considered the subspecies cross-reactivity of Polistes wasps. Others have shown no relationship between the honeybee, vespids (yellow jacket, yellow hornet, white-faced hornet), or Polistes, whereas minor antigenic similarities occur among vespid venoms.14* l5 Over seventeen subspecies of Polistes have been reported, which is potentially a formidable problem. The authors, however, found almost total allergenic similarity between the venoms of the three Polistes subspecies tested. If this holds true for the other Hymenoptera species, collection of venom for diagnosis and therapy will be greatly simplified. Verification of their data by skin testing with the venoms from several Hymenoptera would have added strength to the article since such tests have been shown to be an excellent diagnostic tool in insect allergy.16* l7 Basophil histamine release is not an infallible test; approximately 15% of patients positive by skin test to one or more venoms have basophils that cannot be triggered to release histamine by an immune stimulus (antigen or anti-IgE) . l* Skin testing was not possible for the authors nor is it available as yet to physicians faced with frightened patients in need of an answer. This is a very serious problem. Most clinicians do not have the facilities to perform diagnostic histamine release or RAST assays whereas skin testing is routine. The evidence against the diagnostic utility of whole body extract skin tests leaves the practitioner in an untenable situation which will be improved only as preparations of venoms are made available. The necessity for definitive skin testing is twofold: (1) the patients potentially at risk will be defined and the causitive insect(s) known; (2) if the results in a similar syndrome, penicillin hypersensitivity, can be extended to insect allergy, then negative skin tests will be equally informative. In penicillin allergy, less than 1% of history-positive, skin test-negative patients experience systemic symptoms when re-exposed to the drug.is* 2oIn our experience over 50% of patients with a clear history of a systemic reaction have negative venom skin tests due to the decrease in IgE antibody with time. A large number of patients would thus be relieved of their fear of being stung and would not begin extended and perhaps unnecessary therapy. Under the auspices of the National Institute of Allergy and Infectious Diseases, venom solutions for skin testing have been prepared for distribution to Allergic Disease Centers throughout the United States. Once this plan is effected, diagnostic skin test capability will be available in large sections of this country, easing the problem to some extent. Until
J. ALLERGY
CLIN. IMMUNOL. OCTOBER 1977
standardized test solutions are within the reach of all practicing allergists, however, the application of extensive basic and clinical research efforts to improve patient care will not be possible. REFERENCES 1. Benson, R. L., and Semenov, H.: Allergy in its relation to bee sting, J. ALLERGY 1:105, 1930. 2. Loveless, M. H., and Fackler, W. R.: Wasp venom allergy and immunity, Ann. Allergy 14:347, 1956. 3. Loveless, M. H.: Immunization in wasp-sting allergy through venom repositories and periodic stings, J. Immunol. 89:204, 1962. 4. Foubert, E. L., Jr., and Steir, R. A.: Antigenic relationships between honeybees, wasps, yellow hornets, black hornets and yellow jackets, J. ALLERGY 29~13, 1958. 5. O’Connor, R., and Erickson, R.: Hymenoptera antigens: An immunological comparison of venoms, venom sac extracts and whole insect extract, Ann. Allergy 23: 151, 1965. 6. Shulman, S., Bigelsen, F., and Lang, R.: The allergic response to stinging insects: Biochemical and immunologic studies on bee venom and other bee body preparations, J. Immunol. 9629, 1966. 7. insect Allergy Committee of the American Academy of Allergy. Insect sting allergy: Questionaire study of 2,606 cases, J. A. M. A. 193:109, 1965. 8. Ordman, D.: Desensitization against the effects of bee stings, Int. Arch. Allergy Appl. Immunol. 28:366, 1965. 9. Torsney, P. J.: Treatment failure: Insect desensitization, J. ALLERGY CLIN. IMMUNOL. 52~303, 1973. 10. Schwartz, H.: Skin sensitivity in insect allergy, J. A. M. A. 194~703,1965. 11. Bernton, H. S., and Brown, H.: Studies on the Hymenoptera. I. Skin reactions of normal persons to honeybee (Apis nell. fera) extract, J. ALLERGY 36~315, 1966. 12. Sobotka, A. K., Valentine, M. D., Benton, A., and Lichtenstein, L. M.: Allergy to insect stings. I. The diagnosis of IgEmediated Hymenoptera sensitivity by venom-induced histamine release, J. ALLERGY CLIN. IMMUNOL. 53:170, 1974. 13. Hunt, K. J., Yunginger, J., Valentine, M. D., Sobotka, A. K., and Lichtenstein, L. M.: Sensitization as a result of Hymenoptera whole body extract treatment, J. ALLERGY CLIN. IMMUNOL. (Submitted for publication.) 14. Kern, F., Sobotka, A. K., Valentine, M. D., Benton, A., and Lichtenstein, L. M.: Allergy to insect stings. Ill. Allergenic cross-reactivity among the vespid venoms, J. ALLERGY CLIN. IMMUNOL. 57~554, 1976. 15. King, T. P.: Personal communication. 16. Hunt, K. J., Valentine, M. D., Sobotka, A. K., and Lichtenstein, L. M.: Diagnosis of allergy to stinging insects by skin testing with Hymenoptera venoms, Ann. Intern. Med. 85:56, 1976. 17. Zelesnick, L. D., Hunt, K. J., Sobotka, A. K., Valentine, M. D., Trippett, L. O., and Lichtenstein, L. M.: Diagnosis of Hymenoptera hypersensitivity by skin testing with Hymenoptera venoms, J. ALLERGY CLIN. IMMUNOL. 59~2, 1977. 18. Conroy, M. C., Adkinson, N. F., Jr., Sobotka, A. K., and Lichtenstein, L. M.: “Releasability” of histamine from human basophils, Fed. Proc. 36:1216, 1977. 19. Levine, B. B., and Zolov, D. M.: Prediction of penicillin allergy by immunological tests, J. ALLERGY 43:231, 1969. 20. Adkinson, N. F., Jr., Thompson, W. L., Maddrey, W. C., and Lichtenstein, L. M.: Routine use of penicillin skin testing on an inpatient service, N. Engl. J. Med. 285:22, 1971.