Biphasic local reaction to a new insulin (U-100) Norman Minars, Richmond, T/‘a.
M.D.,
Yao Shi Fu, M.D.,
and
Mario
R. Escobar,
Ph.D.
The phenomenon of 1ocalCed insulin reaction is destibed and illustrated by the report of a case. The patient’s unuszcal response m&tea of an “early” and a of sections from skin biopsies performed 12 and 36 hr following insulin injection showed active proliferation of capillaries in the dermis and subcutaneous tissue. The capillaries wet’c lined by swollen endothelial cells. Heavy infiltration of eosinophils, mixed with a smaller number of neutrophils and lymphocytes, was present in the edematous perivascular spaces, as well as the surrounding tissue of the sweat glands and hair follicles (Fig. 1). ;I skin biopsy performed 4 wk later revealed that the perivascular cellular infiltrate had become even more pronounced and consisted mainly of lymphocytes and plasma cells. Mast cells, macrophages, neutrophils, and eosinophils wrre also present, but in smaller numbers (Fig. 2 !. Immunofluorescent studies on sections of skin biopsies at 12 hr, 36 hr, and 4 wk after insulin injection lvere carried out according to conventional techniques with goat antisera to human IgG, IgA, IgM, and I&C-globulin conjugated with fluorescein isothiocyanatc (FITC). Ap’ propriate control specimens were also examined. Results from these studies were c~onsistently negative.
COMMENTS It is unlikely that the response of our patient was nonspecific because nonspecific reactions usually occur without prior sensitization8 and generally when the intradermal instead of the subcutaneous route is used.5T s Moreover, nonspecific reactions are extremely rare or absent with insulin of extremely high purity, such as the one to which this patient reacted. The histologic appearance of our patient with heavy infiltration of eosinophils was similar to cutaneous allergic responses involving 1gE.O The absence of fibrinoid necrosis of the blood vessels, the lack of leukocytoclastic reaction, and the failure to demonstrate deposition of IgG, IgM, IgA, and B,C within the vascular endothelium and in the cytoplasm of the perivascular inflammatory cells militate against a type III response (Arthus phenomenon). The “late” response, however, appeared to be less characteristic of an immediate allergic reaction on the basis of histologic studies. The time of onset, negative skin tests, and the lack of granulomas negated a cell-mediated response. It is interesting that, according to Dolovitch and associates,” the late response could be related to tissue damage dependent on IgE wherehy there could be a “local” persistence of immunologic
VOLUME NUMBER
56 5
Biphasic
local reaction
to a new insulin (U-100)
415
reactants producing prolonged stimulation of mast cells at the reaction site. The acute reaction might also result in the liberation or production of undefined mediators that have prolonged effects. Another alternative is based on the role of the infiltrating cells. Eosinophilic leukocytes might play a role analogous to that of the neutrophil in immune complex reactions and prolong or amplify the early acute response. Nevertheless, the present study lacks acceptable evidence to support the immune etiology of the local insulin reaction observed. Unlike the other reports cited, direct skin tests and passive cutaneous transfer were consistently negative. REFERENCES 1 Patterson, R., Lucerna, G., Metz, R., and Roberts, M.: Reaginic antibody against insulin. Demonstration of antigenic distinction between native and extracted insulin, J. Immunol. 103: 1061, 1969. 2 Coleman, W. P., Derbes, V. I., and Brown, E. T.: Insulin allergy, Ann. Allergy 29: 383, 1971. 3 Delvin, J. G., and O’Donavon, 0. K.: Preferential beef/pork insulin binding capacity, Diabetes 15: 790, 1966. 4 Lawrence, R. D.: Local insulin reactions, Lancet 1: 1125, 1925. 5 Paley, R., and Tunbridge, R. E.: Dermal reactions to insulin therapy, Diabetes 1: 22, 1952. 6 Dolovich, J., Schnatz, J. D., Reisman, R. E., Yagi, Y., and Arbesman, C. E.: Insulin allergy and insulin resistance: Case report with immunologic studies, J. ALLERGY 46: 127, 1970. 7 Galloway, J. A., and Root, M. A.: New forms of insulin, Diabetes 2l(suppl. 2): 637, 1972. 8 Gelfand, M. L., Fabrykant, M., and Ashe, B. I.: Sensitivity tests to insulin in patients with local skin lesions from insulin, Proc. Sot. Exp. Biol. Med. 86: 258, 1954. 9 Dolovich, J., Hargreave, F. E., Chalmers, R., Shier, K. J., Gauldie, J., and Bienenstock, J.: Late cutaneous allergic responses in isolated IgE-dependent reactions, J. ALLERGY CLIN.
IMJWNOL. 52: 38,1973.
M.D.,
Yao Shi Fu, M.D.,
and
Mario
R. Escobar,
Ph.D.
The phenomenon of 1ocalCed insulin reaction is destibed and illustrated by the report of a case. The patient’s unuszcal response m&tea of an “early” and a of sections from skin biopsies performed 12 and 36 hr following insulin injection showed active proliferation of capillaries in the dermis and subcutaneous tissue. The capillaries wet’c lined by swollen endothelial cells. Heavy infiltration of eosinophils, mixed with a smaller number of neutrophils and lymphocytes, was present in the edematous perivascular spaces, as well as the surrounding tissue of the sweat glands and hair follicles (Fig. 1). ;I skin biopsy performed 4 wk later revealed that the perivascular cellular infiltrate had become even more pronounced and consisted mainly of lymphocytes and plasma cells. Mast cells, macrophages, neutrophils, and eosinophils wrre also present, but in smaller numbers (Fig. 2 !. Immunofluorescent studies on sections of skin biopsies at 12 hr, 36 hr, and 4 wk after insulin injection lvere carried out according to conventional techniques with goat antisera to human IgG, IgA, IgM, and I&C-globulin conjugated with fluorescein isothiocyanatc (FITC). Ap’ propriate control specimens were also examined. Results from these studies were c~onsistently negative.
COMMENTS It is unlikely that the response of our patient was nonspecific because nonspecific reactions usually occur without prior sensitization8 and generally when the intradermal instead of the subcutaneous route is used.5T s Moreover, nonspecific reactions are extremely rare or absent with insulin of extremely high purity, such as the one to which this patient reacted. The histologic appearance of our patient with heavy infiltration of eosinophils was similar to cutaneous allergic responses involving 1gE.O The absence of fibrinoid necrosis of the blood vessels, the lack of leukocytoclastic reaction, and the failure to demonstrate deposition of IgG, IgM, IgA, and B,C within the vascular endothelium and in the cytoplasm of the perivascular inflammatory cells militate against a type III response (Arthus phenomenon). The “late” response, however, appeared to be less characteristic of an immediate allergic reaction on the basis of histologic studies. The time of onset, negative skin tests, and the lack of granulomas negated a cell-mediated response. It is interesting that, according to Dolovitch and associates,” the late response could be related to tissue damage dependent on IgE wherehy there could be a “local” persistence of immunologic
VOLUME NUMBER
56 5
Biphasic
local reaction
to a new insulin (U-100)
415
reactants producing prolonged stimulation of mast cells at the reaction site. The acute reaction might also result in the liberation or production of undefined mediators that have prolonged effects. Another alternative is based on the role of the infiltrating cells. Eosinophilic leukocytes might play a role analogous to that of the neutrophil in immune complex reactions and prolong or amplify the early acute response. Nevertheless, the present study lacks acceptable evidence to support the immune etiology of the local insulin reaction observed. Unlike the other reports cited, direct skin tests and passive cutaneous transfer were consistently negative. REFERENCES 1 Patterson, R., Lucerna, G., Metz, R., and Roberts, M.: Reaginic antibody against insulin. Demonstration of antigenic distinction between native and extracted insulin, J. Immunol. 103: 1061, 1969. 2 Coleman, W. P., Derbes, V. I., and Brown, E. T.: Insulin allergy, Ann. Allergy 29: 383, 1971. 3 Delvin, J. G., and O’Donavon, 0. K.: Preferential beef/pork insulin binding capacity, Diabetes 15: 790, 1966. 4 Lawrence, R. D.: Local insulin reactions, Lancet 1: 1125, 1925. 5 Paley, R., and Tunbridge, R. E.: Dermal reactions to insulin therapy, Diabetes 1: 22, 1952. 6 Dolovich, J., Schnatz, J. D., Reisman, R. E., Yagi, Y., and Arbesman, C. E.: Insulin allergy and insulin resistance: Case report with immunologic studies, J. ALLERGY 46: 127, 1970. 7 Galloway, J. A., and Root, M. A.: New forms of insulin, Diabetes 2l(suppl. 2): 637, 1972. 8 Gelfand, M. L., Fabrykant, M., and Ashe, B. I.: Sensitivity tests to insulin in patients with local skin lesions from insulin, Proc. Sot. Exp. Biol. Med. 86: 258, 1954. 9 Dolovich, J., Hargreave, F. E., Chalmers, R., Shier, K. J., Gauldie, J., and Bienenstock, J.: Late cutaneous allergic responses in isolated IgE-dependent reactions, J. ALLERGY CLIN.
IMJWNOL. 52: 38,1973.
