Evidence for Association

Biologic Plausibility

A study by Kovalskaya (1967) demonstrated that it is possible to sensitize mice with large intraperitoneal doses of DT or DPT to fatal anaphylactic reactions with large doses of the monovalent tetanus, diphtheria, or pertussis antigen.

Several studies in humans have demonstrated the frequent development of tetanus and diphtheria IgE antibodies after booster immunization (Cogne et al., 1985; Nagel et al., 1977). However, a study of in vitro basophil degranulation in subjects with tetanus-specific serum IgE was entirely negative (Miadonna, 1980). Miadonna examined the role of IgG antibodies that might block binding of antigen to IgE on basophils. However, added IgG did not seem to affect the degranulation of basophils after exposure to tetanus toxoid, and the authors concluded that, in their system, the IgE receptor on basophils has a low affinity for tetanus-specific IgE antibodies, thus explaining the very low rate of allergic reactions (0.06 percent) that they observed in a study of 25,000 children immunized with tetanus toxoid (Miadonna and Falagiani, 1978). Facktor et al. (1973) and Vellayappan and Lee (1976) studied 70 and 38 individuals, respectively, who had no clinical history of reactions to tetanus toxoid and found a high incidence of immediate cutaneous hypersensitivity reactions (63 percent in both studies). Conversely, Jacobs et al. (1982) skin tested and challenged with tetanus toxoid 740 individuals with a history of adverse reactions to tetanus toxoid, including 95 individuals who reported an ''anaphylactoid" reaction. Ninety-four of the 95 individuals with anaphylactoid reactions had negative skin tests. The one patient with a positive skin test tolerated full tetanus toxoid challenge without adverse effects. Thus, although a small number of cases of anaphylaxis apparently related to tetanus toxoid have been observed (see below), the relation between these reactions and specific IgE antibodies and the accepted measurements of immediate hypersensitivity remains unclear.

In a study of 158,230 airmen who received two injections of alum-precipitated Td (<2 Lf of diphtheria toxoid), 101 were referred for evaluation for an allergic reaction or any reaction (local or systemic) severe enough to interfere with normal activities (Smith and Wolnisty, 1962). No apparent relation between the symptoms and the immunization was found in 53 of the airmen; all 53 received boosters of Td without adverse effects. Forty-eight were skin tested intradermally for immediate wheal and flare reactions. None had a reaction to diphtheria toxoid, but two had a reaction to tetanus toxoid. These two individuals had a history of urticaria that developed within hours after receiving Td. They were immunized with diphtheria toxoid without adverse effects. The remaining 46 subjects each received



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