5
Diphtheria and Tetanus Toxoids

BACKGROUND AND HISTORY

Tetanus

The causative agent of tetanus, Clostridium tetani, is a gram-positive, spore-forming anaerobic bacillus. C. tetani produces two exotoxins, tetanolysin and tetanospasmin. Tetanus results from the latter toxin, one of the most potent toxins on a weight basis (Wassilak and Orenstein, 1988). Tetanus toxin enters the nervous system at peripheral nerve endings. The toxin binds to a receptor, is internalized by endocytosis, and is transported to nerve cell bodies, primarily motoneurons, in the central nervous system (Fishman and Carrigan, 1988). Tetanus toxin appears to work presynaptically to affect neurotransmitter release (Bergey et al., 1987). The mode of action of tetanus toxin is similar to that of another well-known toxin, botulinum toxin, which is also produced by an anaerobic organism (Simpson, 1986). The mechanisms of action of these toxins have not been fully elucidated.

Early studies in experimental animals demonstrated that protective neutralizing antibodies could be elicited by repeated inoculations with a minute amount of toxin (Wassilak and Orenstein, 1988). These antisera also could provide passive protection when administered to nonimmune recipients. In 1926, Ramon and Zoeller immunized human subjects with a toxoid prepared by formaldehyde and heat treatment of the toxin. Although the pro-



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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 5 Diphtheria and Tetanus Toxoids BACKGROUND AND HISTORY Tetanus The causative agent of tetanus, Clostridium tetani, is a gram-positive, spore-forming anaerobic bacillus. C. tetani produces two exotoxins, tetanolysin and tetanospasmin. Tetanus results from the latter toxin, one of the most potent toxins on a weight basis (Wassilak and Orenstein, 1988). Tetanus toxin enters the nervous system at peripheral nerve endings. The toxin binds to a receptor, is internalized by endocytosis, and is transported to nerve cell bodies, primarily motoneurons, in the central nervous system (Fishman and Carrigan, 1988). Tetanus toxin appears to work presynaptically to affect neurotransmitter release (Bergey et al., 1987). The mode of action of tetanus toxin is similar to that of another well-known toxin, botulinum toxin, which is also produced by an anaerobic organism (Simpson, 1986). The mechanisms of action of these toxins have not been fully elucidated. Early studies in experimental animals demonstrated that protective neutralizing antibodies could be elicited by repeated inoculations with a minute amount of toxin (Wassilak and Orenstein, 1988). These antisera also could provide passive protection when administered to nonimmune recipients. In 1926, Ramon and Zoeller immunized human subjects with a toxoid prepared by formaldehyde and heat treatment of the toxin. Although the pro-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality tective level of antibody could not be assessed directly in human subjects (by challenge with active toxin), two early workers in this field immunized themselves with the tetanus toxoid and then challenged themselves with two to three fatal doses of tetanus toxin. They were protected by their prechallenge serum levels of 0.007 and 0.01 American units of tetanus toxoid per ml (Wolters and Dehmel, 1942). In 1950, the World Health Organization (WHO) reset the international unit (IU) to equal the American unit (see the section Biologic Events Following Immunization below). Two types of tetanus toxoid are available in the United States: fluid and adsorbed. The adsorbed vaccines contain less than 1.25 mg of aluminum and 4 to 10 flocculation units (Lf) of toxoid per 0.5-ml dose. (The quantity of toxoid is measured by in vitro flocculation when toxoid is mixed with a known amount of antitoxin, and the results are recorded as the limit of flocculation [Lf].) The fluid preparations contain 4 to 5 Lf of toxoid. All tetanus toxoids in the United States contain 0.02 percent formaldehyde and 0.1 percent thimerosal. Some investigators have noted an increased rate of severe local reactions and abscess formation when adsorbed diphtheria toxoid or diphtheria and tetanus toxoids for pediatric use (children under 7 years of age) (DT) were used (e.g., 30 percent adsorbed versus 8 percent fluid) (Collier et al., 1979; Holden and Strang, 1965). However, others have not corroborated these findings and note that adsorbed toxoids have similar reaction rates as long as the injections are given intramuscularly rather than subcutaneously. In addition, adsorbed toxoids offer the benefit of enhanced immunogenicity (Jones et al., 1985; Relihan, 1969; Trinca, 1965; White, 1980; White et al., 1973). Diphtheria Diphtheria is an acute respiratory infection caused by Corynebacterium diphtheriae. In a nontoxigenic form, the organism may colonize the throat of asymptomatic individuals or may produce mild pharyngitis. However, when the bacterium is infected with a bacteriophage carrying the structural gene for biosynthesis of the toxin responsible for clinical disease, classic diphtheria can result. The clinical presentation includes a fibrinous, adherent pharyngeal membrane and complications of severe systemic toxicity, myocarditis, and peripheral neuritis. Case fatality rates were commonly in the range of 50 percent prior to the availability of antitoxin therapy. It is now known that diphtheria toxin is one of a family of A and B toxins. The A and B fragments of diphtheria toxin are part of a single polypeptide chain. Fragment A ("active") is a potent enzyme that acts intracellularly to block protein synthesis. The only known substrate for fragment A is elongation factor 2, which is involved in catalyzing the movement of ribosomes

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality on eukaryotic messenger RNA. A single molecule of fragment A can kill a cell. Fragment B ("binding") is responsible for the recognition of receptors on mammalian cells and the translocation of fragment A into cells (Uchida, 1986). Protective human antibodies against diphtheria are directed against fragment B (Mortimer, 1988). The protective role of antisera against the toxin was documented by Behring in the late nineteenth century (Holmes, 1940), and the use of diphtheria antiserum raised in horses to treat human diphtheria was introduced a few years later. Active immunization with inactivated toxin in experimental animals was adapted to immunization of humans. Early in the history of immunization against diphtheria, active toxin and antitoxin (prepared in horses) were administered as a mixture. In several reports, fatalities caused by the toxic effects of inadequately neutralized diphtheria toxin occurred in children given these mixtures (Dittmann, 1981b; Wilson, 1967). Following the introduction of toxin neutralization by chemical means (formalin), one report of incomplete detoxification appeared. In Kyoto, Japan, in 1948, 68 of 606 children died following inoculation with a formalin-detoxified vaccine. Free toxin was detected in one batch of the vaccine (Dittmann, 1981b). Currently licensed toxoids produced in the United States are now prepared and tested by procedures specified in the Code of Federal Regulations, and no cases of toxin-related disease have been reported since 1948. Because of the severity of clinical diphtheria and the early recognition that protection was safely induced by immunization with diphtheria toxoid, controlled clinical trials of the efficacy of diphtheria toxoid were never performed. Early in the history of immunization against diphtheria, Schick (1913) introduced a test that correlated with protective immunity, thus making it possible to study both naturally acquired and toxoid-induced immunity. This test consists of the intradermal injection of a small amount of purified toxin. In nonimmune individuals who lack circulating antitoxin, a red, slightly hemorrhagic area appears at the injection site within 48 hours. Individuals with protective levels of antitoxin antibody (>0.01 U/ml) have no local reaction. On the basis of the correlation of a negative Schick test with protective immunity and a correlation between negative Schick test results and a serum antitoxin titer of 0.01 to 0.02 U/ml, one or both of these tests have been used to measure the efficacy of diphtheria immunization protocols that utilize various doses and administration schedules. In the United States, children receive vaccines according to schedules determined by the American Academy of Pediatrics and the Advisory Committee on Immunization Practices. These groups recommend that diphtheria and tetanus toxoids and pertussis vaccine (DPT) be given at ages 2, 4, and 6 months, between ages 15 and 18 months, and between ages 4 and 6 years. The acellular pertussis-containing (DTaP) preparation can be substituted for

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality DPT for the fourth and fifth doses. Diphtheria and tetanus toxoids for pediatric use (DT) should be used in children younger than age 7 years in whom DPT is contraindicated. Tetanus and diphtheria toxoids for adult use (Td) should be used in individuals older than age 7 years. They should be administered every 10 years following the last DPT or DT vaccination. BIOLOGIC EVENTS FOLLOWING IMMUNIZATION Tetanus Following an injection of tetanus toxoid, the recipient develops neutralizing antibodies that prevent the effects of toxin on the nervous system. Antibody levels are now reported in comparison with an international standard set by the WHO as international units per milliliter, and it is generally agreed that a level of 0.01 IU/ml or greater is protective (Wassilak and Orenstein, 1988). Protective levels of antibody are achieved in most children and adults after two doses of tetanus toxoid given 4 or more weeks apart, although children under 1 year of age may require three doses of tetanus toxoid (Barkin et al., 1984, 1985a). However, protective levels are relatively short-lived, particularly in infants and older adults, and thus, a reinforcing (booster) dose is given 6 to 12 months after the primary series of immunizations. Following this booster, long-term immunity usually exceeding 10 years develops (Peebles et al., 1969). Minor local reactions (pain, erythema, swelling of less than 1 cm) occur within 48 hours following 1-80 percent of immunizations with tetanus toxoid (Collier et al., 1979; Jones et al., 1985; White, 1980). The reaction rate varies with the dose and type of toxoid, the number of prior doses of toxoid received, and the method of injection. Severe reactions (>8 cm of erythema or induration) are much less common and are often accompanied by a sore, swollen arm and systemic manifestations such as fever and malaise. Severe reactions occur much more frequently with larger doses of toxoid (McComb and Levine, 1961; Schneider, 1964), and in several studies, severe reactions have been found to correlate with high antibody levels prior to immunization (Collier et al., 1979; Facktor et al., 1973; Korger et al., 1986; Levine and Edsall, 1981; Levine et al., 1961; McComb and Levine, 1961; Relihan, 1969; White et al., 1973). Prior to the recognition of the long duration of immunity, frequent booster doses given after minor wounds or as prophylaxis for factory employees or children attending summer camps led to high levels of antibody. The correlation between severe local reactions and high antibody levels prior to immunization strongly suggests that these reactions may be caused by immune complex formation between antibodies and antigen. In the case of severe local reactions, this is classified as an Arthus reaction, in which

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality immune complexes form locally in the walls of small arteries (Edsall et al., 1967; Eisen et al., 1963; Facktor et al., 1973). In rare cases, it is possible that the immune complexes may form in the circulation, deposit in tissues, and activate complement. This would result in the clinical syndrome of serum sickness. These patients may develop glomerulonephritis, arthritis, and vasculitis. However, some investigators have been unable to confirm a consistent correlation between more severe local reactions and high antibody levels (Holden and Strang, 1965; Jones et al., 1985; White et al., 1973), and thus, it is likely that other factors such as toxoid variables, adjuvants, dose, and host factors may also play a role in the development of severe local reactions. Routine immunization with tetanus toxoid also induces a cellular immune response, and intradermal skin testing with tetanus toxoid frequently is used as a screen for anergy (Gordon et al., 1983; Grabenstein, 1990; Steele et al., 1976). The absence of a delayed-type hypersensitivity response does not imply a lack of protective immunity, and conversely, a positive response does not appear to correlate with clinically important hypersensitivity reactions to the toxoid (Eisen et al., 1963; Facktor et al., 1973; Gold, 1941; Vellayappan and Lee, 1976). Diphtheria In the preimmunization era, many people acquired immunity to diphtheria (and a negative Schick test) presumably by asymptomatic colonization. Also, protective immunity was observed in young infants, most likely on the basis of the presence of transplacentally acquired antibody (Schick, 1913). Diphtheria toxoid adsorbed with aluminum hydroxide or phosphate was shown to be more immunogenic and to produce fewer local reactions than fluid toxoid. The minimum schedule for children was found to be three doses, with the first two doses spaced by 1-2 months and the third dose given 6-12 months later. Booster doses were found to be necessary, particularly in countries where widespread immunization markedly decreased the opportunity for asymptomatic colonization (Bjorkholm et al., 1986; Christenson and Bottiger, 1986; James et al., 1951; Karzon and Edwards, 1988; Rappouli et al., 1988). To maintain protective levels of antitoxin antibody against diphtheria, recall immunization is suggested in older children and adults at 10-year intervals. Early studies of the immune response to immunization against diphtheria revealed that some immune individuals responded to a Schick test with immediate hypersensitivity reactions (wheal and erythema within minutes) or delayed-type hypersensitivity reactions that were maximal at 24-72 hours (Zingher and Park, 1923). An important consequence of this observation

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality was that interpretation of a "positive" Schick reaction to toxin required a control test with purified toxoid. Another implication was that pseudoreactions might predict clinically relevant hypersensitivity to further immunization with diphtheria toxoid (Pappenheimer, 1984). However, not all investigators found a high degree of correlation between Schick test results and adverse reactions (Settergren et al., 1986), and routine testing prior to immunization is impractical. Pappenheimer et al. (1950) demonstrated that a significant proportion of the delayed-type hypersensitivity reactions in previously immunized subjects were against the contaminants in the crude toxoid rather than against the highly purified diphtheria toxin. The role of bacterial cellular fractions in adverse reactions has been confirmed by Relyveld and colleagues (1979, 1980). The problems of high rates of severe local and systemic reactions (fever, malaise, myalgia, headaches, and chills) noted in earlier studies with diphtheria toxoid in older children and adults have been alleviated by (1) the use of improved methods for purifying toxins, (2) reduction of the dose of toxoid (<2 Lf of diphtheria toxoid in Td versus 10-20 Lf in DPT and 10-12 Lf in DT), and (3) the use of adsorbed vaccine (Edsall et al., 1954; Levine et al., 1961; Myers et al., 1982; Smith, 1969). By this approach, the rates of adverse reactions related to hypersensitivity have been very low (Middaugh, 1979; Mortimer et al., 1986; Myers et al., 1982; Sheffield et al., 1978). Mild local reactions (tenderness and swelling at the injection site) occurred in 16 to 27 percent of vaccinees. Erythema, marked swelling, or systemic symptoms occurred in fewer than 2 percent of individuals. ENCEPHALOPATHY Clinical Description Encephalopathy has been used in the literature to characterize a constellation of signs and symptoms reflecting a generalized disturbance in brain function often involving alterations in behavior or state of consciousness, convulsions, headache, and focal neurologic deficit. The annual incidence of encephalitis for the years 1950 to 1981 in Olmsted County, Minnesota was 7.4 per 100,000 (Beghi et al., 1984; Nicolosi et al., 1986). The incidence in children less than 1 year of age was 22.5, in children between 1 and 4 years of age it was 15.2, and in children between 5 and 9 years of age it was 30.2 per 100,000. Other estimates of encephalopathy for children less than age 2 years were somewhat lower than those reported by Beghi et al. (1984) and Nicolosi et al. (1986). Other estimates for annual incidence range from 5 per 100,000 children younger than age 2 years (Walker et al., 1988) to 10 per 100,000 children younger than age 2 years (Gale et al., 1990). For a more complete discussion of encephalopathy, see Chapter 3.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality History of Suspected Association Diphtheria toxin causes a toxic peripheral neuropathy in about 20 percent of cases (Mortimer, 1988), but diphtheria toxin has not been found to be associated with central nervous system (CNS) disease such as encephalopathy. Tetanus is a neurologic disease characterized by severe lower motor neuron hyperexcitability with consequent muscle spasms produced by the potent neurotoxin tetanospasmin (Wassilak and Orenstein, 1988). Diphtheria and tetanus toxoids are generally given together as Td in adults and as DT or DPT (a combination that includes vaccine directed against pertussis) in children. DT and Td differ because of the lower concentration of diphtheria toxoid in the preparation for adults. Monovalent diphtheria and monovalent tetanus toxoids are also available. Pertussis as a clinical disease has long been known to cause encephalopathy, as discussed in detail by the Institute of Medicine (1991). The possibility that immunization against pertussis was responsible for serious adverse neurologic events leading to encephalopathy was raised as early as 1933, with concerns continuing to be reported through the present. Several large epidemiologic studies were designed to study the association between DPT and acute neurologic events in children. From those studies, information regarding DT was also obtained because of the lack of universal acceptance of DPT. The National Childhood Encephalopathy Study (Alderslade et al., 1981) and the North West Thames study (Pollock and Morris, 1983) provide some information on encephalopathy and DT. Additionally, two case-control studies in Italy (Crovari et al., 1984; Greco, 1985) were carried out to investigate a clinical observation that encephalopathy in several children was temporally related to DT immunization. Evidence for Association Biologic Plausibility Although tetanus toxin can reach the CNS, it is not clearly associated with encephalopathy. The neurologic sequelae of tetanus have been described. Symptoms experienced by patients after recovery from tetanus include irritability, sleep disturbances, myoclonus, decreased libido, postural hypotension, and abnormalities on electroencephalograms (Illis and Taylor, 1971). The symptoms disappeared within 2 years of recovery from tetanus. These were attributed by the author as secondary to the action of tetanus toxin on inhibitory synapses in the CNS. The neurologic consequences of diphtheria are primarily peripheral neuropathy.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Case Reports, Case Series, and Uncontrolled Observational Studies The North West Thames study by Pollock and Morris (1983), an uncontrolled cohort study, was a collection of reports of all reactions to vaccines in the North West Thames region of England and Wales. It was designed to intensify the reporting of severe manifestations, particularly neurologic complications, after childhood immunization between January 1975 and December 1981. Of 400,500 doses of DT and oral polio vaccine (OPV) (133,500 children completing a primary series of three doses of vaccine) and 221,000 single booster doses of DT given at school entry, seven children had seizures without neurologic damage and were well at follow-up. Three children with other neurologic conditions were identified; one child (9 months old) had infantile spasms predating vaccination, another child (9 years old) had a seizure with hemiplegia 1 day after receipt of DT but was normal on follow-up, and another child (7 months old) developed hemiparesis 14 days after receipt of DT and was normal on follow-up. None of these neurologic events was considered to be encephalopathic. Because it was felt that reactions that occurred after vaccination with DT were being underreported in the first part of the North West Thames study (compared with the reporting of reactions that occurred after vaccination with DPT), an alternative method of study was undertaken on the basis of a hospital activity analysis of hospitals in the North West Thames region during 1979. Children under 2 years of age were included in the study if their diagnosis at the time of discharge included a neurologic event. No control group was used. Of 18,000 children who completed a primary series of DT (approximately 54,000 doses of DT were administered), 18 children had seizures (all febrile) within 28 days of DT immunization and 3 children had some other neurologic disease that developed within 28 days of DT immunization. Two of these children had focal seizures at 22 and 24 days after DT immunization, and the other child died of encephalopathy 28 days after DT immunization. Insufficient detail was given to describe the case of encephalopathy. Several clinical trials compared DT and DPT (therefore, they are considered uncontrolled cohort studies for DT), and they showed that there were no serious neurologic adverse events after receipt of DT. Those studies, by Cody et al. (1981) and Barkin et al. (1985b), had only very small samples of those immunized with DT (784 and 40 subjects, respectively) and therefore do not provide much additional knowledge of the adverse events following immunization with DT. Quast and colleagues (1979) found in the records of Behringwerke (a pharmaceutical firm in the former West Germany) a case report of a 36-year-old female who developed polyneuromyeloencephalopathy 5 days after receiving her first dose of aluminum-adsorbed tetanus toxoid in 1976. The

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality authors provided no clinical information other than the fact that she recovered completely. Several small case series described in the literature looked for adverse events following immunization with both DPT and DT (Feery, 1982; Waight et al., 1983). Those studies showed no adverse neurologic events following receipt of DT, although the sample sizes in those two studies were small (335 and 221 subjects, respectively). The following cases were reported in the Vaccine Adverse Event Reporting System (VAERS) between November 1990 and July 1992: a 50-year-old male who developed syncope, visual disturbance, and hypoglycemia 1 day after receiving tetanus toxoid; a 14-year-old male who developed encephalitis and transverse myelitis 2.5 months following Td administration; and a 17-year-old male who developed lymphocytic meningoencephalitis 10 days following receipt of Td and measles-mumps-rubella vaccine (MMR). Controlled Observational Studies The best observational case-control study that provides information about immunization with DT and association with neurologic illness is the National Childhood Encephalopathy Study (NCES) (Alderslade et al., 1981), which was undertaken because of concerns about possible adverse events following receipt of pertussis vaccine. That study identified children aged 2-36 months who were admitted to a hospital with neurologic illness during the 3 years from July 1976 to June 1979 in England, Scotland, and Wales. The first 1,000 of 1,182 cases identified during that time were studied. For each case there were two ''at-home'' controls matched for age, sex, and area of residence. No statistically significant association with DT immunization and neurologic adverse events was found in cases compared with controls. On the basis of the data in Table V.15 on page 122 of the NCES (Alderslade et al., 1981), the odds ratio (OR) is 0.92 (95 percent confidence interval [CI], 0.64-1.30). However, as with infantile spasms, a nonsignificantly higher rate of exposure to DT was observed within the 7 days prior to the date of onset of illness in the case patients, and a correspondingly lower rate of exposure was observed between more than 7 and less than 28 days prior to onset. Because nearly one-third of the cases had prolonged febrile convulsions, the excess rate of exposure to DT within 7 days, if real, may merely reflect the tendency of DT vaccination to cause fever. Greco (1985) carried out a case-control study in the Campania (Naples) region of Italy from January 1980 to February 1983 to test the association between encephalopathy and immunization with DT. The Italian Ministry of Health had received reports that described several cases of encephalopathy in children who had received DT within the week prior to illness, and those reports were the impetus for the study. A case was defined as a patient

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality between the ages of 3 and 48 months who was admitted to the Santobono Hospital intensive care unit during the study period with one or more of the following diagnoses: coma of unknown cause, Reye syndrome, convulsions of unknown cause, respiratory distress with coma from an unknown cause, and death or stupor from an unknown cause. Forty-five patients that met the case definition were identified, and for each case there were four matched controls: two hospital controls and two residential controls. Hospital controls were matched to cases by age, sex, and date of admission; residential controls were matched by age, sex, and place of residence. The authors found that 64 percent of the case patients had been immunized with DT during the month prior to hospitalization, whereas 10 percent of hospital controls and 13 percent of residence controls had been immunized with DT. The reported ORs were 40.9 (95 percent CI, 6.3-102.5) for immunization with DT within the month prior to hospitalization and 92.6 (95 percent CI, 35.1-244.1) within the week prior to hospitalization. The study by Greco (1985) has many methodologic problems. First and foremost, the cases leading to the Italian Ministry of Health's alert concerning the possible association between DT vaccination and encephalopathy served as part of the case group for the study. Additionally, cases were selected without blinding with respect to their prior immunization status. As described in the article, many of the case patients had elevated transaminase and ammonia levels but had normal cerebrospinal fluid (CSF) findings, suggesting the diagnosis of Reye syndrome. To the extent that DT may have been given to children with concomitant influenza or other viral illnesses, the occurrence of local or febrile reactions may have led to treatment with aspirin and. secondarily, the development of Reye syndrome. No information on aspirin use was given in the article describing the study. In addition, case DT recipients were twice as likely as control DT recipients to have received OPV simultaneously. In response to the same reports that led to the study by Greco (1985), another case-control study (Crovari et al., 1984) was undertaken in the Luguria (Genoa) region of Italy to assess the association between recent DT immunization and coma or complicated convulsions. The study of Crovari et al. (1984) drew its cases from admissions to the intensive care unit, infectious disease ward, and general ward of the hospital of the Istituto G. Gaslini in Genoa between January 1980 and June 1983. The case patients were between 3 and 48 months of age and were admitted with coma, complicated convulsions of unknown etiology, or both. Children with known epilepsy or febrile convulsions were supposedly excluded from the case group, but the authors later state (in the results) that the majority of patients presented with "hyperpyrexia." Twenty-nine cases were identified, and each case was matched with four controls (two inpatient and two outpatient) by sex and age for inpatient controls and by age, sex, and residence for

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality outpatient controls. The study did not show a statistically significant association between receipt of DT and coma or complicated convulsions (matched OR, 1.6; 95 percent CI, 0.54-4.74). However, the outpatient controls were randomly selected from records of vaccinated children. This would inflate exposure rates among the outpatient control group and perhaps create a negative bias in the odds ratio. Unpublished information provided by the authors permitted a separate (unmatched) analysis for the cases and inpatient controls, which revealed an unmatched OR of 2.16 (95 percent CI, 0.37-12.49). A meta-analysis combining the data from the NCES and the cases and inpatient controls from the study of Crovari et al. (1984) yields a Mantel-Haenszel OR of 0.95 (95 percent CI, 0.68-1.34). Controlled Clinical Trials No controlled clinical trials have compared DT recipients with an appropriate control. Causality Argument There is some biologic plausibility that tetanus toxoid-containing preparations might cause encephalopathy, on the basis of the evidence of Illis and Taylor (1971) that tetanus toxin has been associated with CNS sequelae. The case reports and case series reviewed above offer no convincing evidence for the occurrence of encephalopathy following immunization with DT. Three case-control studies addressed the question of a possible relation between DT immunization and encephalopathy. The best of the controlled observational studies is the NCES (Alderslade et al., 1981). The authors of that study did not detect an association between the occurrence of acute neurologic illness and receipt of DT (OR, 0.92; 95 percent CI, 0.64-1.30), nor did a meta-analysis combining the NCES results with those based on cases and inpatient controls in the study by Crovari et al. (1984) (OR, 0.95; 95 percent CI, 0.68-1.34). Therefore, the combined evidence strongly suggests that no relation exists between immunization with DT and the onset of acute neurologic illness. The possibility of lot-specific reactions to DT, as has been demonstrated for DPT preparations (Baraff et al., 1989), suggests that studies could be more revealing if the vaccines were tracked by lot. (See Chapter 11 for suggestions for further research.) If the evidence favors rejection of a causal relation between DT and acute encephalopathy, then in the committee's judgment the evidence favors rejection of a causal relation between DT and chronic encephalopathy and between Td and tetanus toxoid alone and encephalopathy.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality was pronounced dead on arrival and the other was in shock and died several hours later. No free diphtheria toxin was found in the vaccine, and the histopathology was consistent with death from anaphylactic shock. One additional case of anaphylaxis associated with diphtheria toxoid has been reported (Ovens, 1986). That report described a 32-year-old woman who also received inactivated polio vaccine and tetanus toxoid (Table 5-1). She denied a prior history of immunization, so the possibility of a reaction to another vaccine component could not be ruled out, and no further analysis was performed. Two cases of anaphylaxis following Td immunization were reported through VAERS (submitted between November 1990 and July 1992). Neither case met the committee's criteria for anaphylaxis. In one instance, the patient developed dyspnea alone 3 hours after immunization; in the other, the patient had an apparent vasovagal reaction that lasted 15 minutes. In the MSAEFI reports of adverse events with follow-up information following administration of single vaccines, 1 case of anaphylaxis was reported following administration of DT, 16 were reported following Td, and none were reported following tetanus toxoid. All 17 patients recovered. Clinical details for assessing whether these cases met the criteria for anaphylaxis described above were not available. In the previous Institute of Medicine report on the adverse effects of DPT (Institute of Medicine, 1991), the available evidence indicated a causal relation between one or more of the vaccine components and anaphylaxis. The pertussis component could not be implicated specifically. Christensen (1972) reported the results of a prospective review of all side reactions to diphtheria and tetanus toxoids administered in Denmark between 1952 and 1970. In that country, the author notes that a centralized reporting system and a single vaccine supplier (State Serum Institute, Copenhagen) provide a mechanism for a "fairly good estimate" of the frequency of serious reactions to vaccine. Among 2.5 million adults who received monovalent tetanus toxoid and 1.1 million children who received DT, two cases of "acute collapse" were reported. Both reactions occurred in children (4 and 11 years of age) after receiving their first dose of tetanus toxoid. Each child developed "shock'' but recovered completely after treatment with epinephrine. Although the reactions were reported as anaphylactic, the author noted that neither patient had "specific stigmata'' of anaphylaxis. In a prospective study comparing adverse events after primary immunization with DPT (6,004 infants) and DT (4,024 infants) (Pollock et al., 1984), 13 children developed pallor and cyanosis within 5 minutes to 24 hours. Nine cases occurred following administration of DPT and four occurred following administration of DT. The episodes did not resemble anaphylaxis and resolved spontaneously. In the 7-year survey of vaccine reactions in the North West Thames region conducted by Pollock and Morris

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality (1983), two cases of anaphylaxis or collapse were reported during the primary series of DT immunizations (133,500 children; each child completed a course of three doses), six followed booster DT immunization (221,000 children; one dose), and one followed immunization with tetanus toxoid (the number immunized was not given). Five of these children were described as becoming cold, clammy, and pulseless, but all "recovered rapidly." The other four children were said to have mild manifestations, including slight facial swelling, pallor, and vasovagal attacks, from which they recovered. From the available descriptions, none of the events in either study resembled anaphylaxis as defined for the present analysis. Controlled Observational Studies None. Controlled Clinical Trials None. Causality Argument Studies in experimental animals and data collected from human subjects suggest that both tetanus and diphtheria toxoids can induce immediate hypersensitivity reactions. Although elevated levels of tetanus-and diphtheria-specific IgE antibodies are frequently demonstrated in immunized individuals, neither these antibodies nor immediate skin reactivity correlates well with clinical manifestations of hypersensitivity to the toxoids. Nine cases of anaphylaxis temporally related to immunization with tetanus toxoid alone have been reported since the removal of contaminating proteins. Thus, it appears that tetanus toxoid can cause anaphylaxis. No cases of anaphylaxis associated with administration of diphtheria toxoid alone have been reported. Conclusion The evidence establishes a causal relation between tetanus toxoid and anaphylaxis. If the evidence establishes a causal relation between tetanus toxoid and anaphylaxis, then in the committee's judgment the evidence establishes a causal relation between DT or Td and anaphylaxis. Because the conclusions are not based on controlled studies, no estimate of incidence or relative risk is available. It would seem to be low.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Risk-Modifying Factors Individuals with a history of immediate hypersensitivity reactions to previous doses of vaccines containing tetanus toxoid may be at increased risk of subsequent reactions. In such individuals, special precautions have been suggested (American Academy of Pediatrics, Committee on Infectious Diseases, 1991; Jacobs et al., 1982; Wassilak and Orenstein, 1988). DEATH A detailed discussion of the evidence regarding death following immunization can be found in Chapter 10. Only the causality argument and conclusions follow. See Chapter 10 for details. Causality Argument The evidence favors rejection of a causal relation between DPT and sudden infant death syndrome (SIDS) (Institute of Medicine, 1991). Pollock et al. (1984) presented data suggesting that the relative risk of SIDS after DPT versus that after DT is not significantly different from 1. In the committee's judgment the evidence favors rejection of a causal relation between DT and SIDS. The evidence favors acceptance of a causal relation between DT, Td, and tetanus toxoid and GBS. The evidence establishes a causal relation between DT, Td, and tetanus toxoid and anaphylaxis. Both GBS and anaphylaxis can be fatal. The only well-documented cases of death causally related to immunization with tetanus toxoid, DT, or Td are attributable to anaphylaxis; the evidence regarding death as a consequence of GBS that temporally followed administration of one of these toxoids is very limited. In the committee's judgment DT, Td, or tetanus toxoid may rarely cause fatal GBS or anaphylaxis. There is no evidence or reason to believe that the case fatality rate from vaccine-associated GBS or anaphylaxis would differ from the case fatality rate for these adverse events associated with any other cause. Reports of death from all other causes are not clearly linked to the preceding immunization. No cases of death were reported by Christensen (1972) in Denmark between 1952 and 1970, a time during which 2.5 million doses of monovalent tetanus toxoid, 2.67 million doses of DT, and 1.1 million doses of Td were given. No cases of death associated with tetanus toxoid, DT, or Td were reported through MSAEFI between 1979 and 1990. During that time, approximately 1.3 million doses of DT and 29 million doses of Td were distributed.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Conclusion The evidence establishes a causal relation between DT, Td, and tetanus toxoid and death from anaphylaxis. Although this conclusion is based on direct evidence, it is not based on controlled studies and no relative risk can be calculated. However, the risk of death from anaphylaxis following DT, Td, or tetanus toxoid would appear to be extraordinarily low. The evidence favors acceptance of a causal relation between DT, Td, and tetanus toxoid and death from GBS. This conclusion is not based on controlled studies and no relative risk can be calculated. However, the risk of death from GBS following DT, Td, or tetanus toxoid would seem to be extraordinarily low. The evidence favors rejection of a causal relation between DT and SIDS. The evidence is inadequate to. accept or reject a causal relation between tetanus toxoid, DT, or Td and death from causes other than those listed above. REFERENCES Alderslade R, Bellman MH, Rawson NS, Ross EM, Miller DL. The National Childhood Encephalopathy Study: a report on 1000 cases of serious neurological disorders in infants and young children from the NCES research team. In: Department of Health and Social Security. Whooping Cough: Reports from the Committee on the Safety of Medicines and the Joint Committee on Vaccination and Immunization. London: Her Majesty's Stationery Office; 1981. American Academy of Pediatrics, Committee on Infectious Diseases. The Red Book. Report of the Committee on Infectious Diseases, 22nd edition. Elk Grove, IL: American Academy of Pediatrics; 1991. Baraff LJ, Manclark CR, Cherry JD, Christenson P, Marcy SM. Analyses of adverse reactions to diphtheria and tetanus toxoids and pertussis vaccine by vaccine lot, endotoxin content, pertussis vaccine potency and percentage of mouse weight gain. Pediatric Infectious Disease Journal 1989;8:502-507. Barkin RM, Samuelson IS, Gotlin LP. DTP reactions and serologic response with a reduced dose schedule. Journal of Pediatrics 1984; 105:189-194. Barkin RM, Pichichero ME, Samuelson JS, Barkin SZ. Pediatric diphtheria and tetanus toxoids vaccine: clinical and immunologic response when administered as the primary series. Journal of Pediatrics 1985a; 106:779-781. Barkin RM, Samuelson JS, Gotlin LP, Barkin SZ. Primary immunization with diphtheria-tetanus toxoids vaccine and diphtheria-tetanus toxoids-pertussis vaccine adsorbed: comparison of schedules. Pediatric Infectious Disease 1985b;4:168-171. Baust W, Meyer D, Wachsmuth W. Peripheral neuropathy after administration of tetanus toxoid. Journal of Neurology 1979;222:131-133. Beghi E, Kurland LT, Mulder DW. Incidence of acute transverse myelitis in Rochester, Minnesota, 1970-1980, and implications with respect to influenza vaccine. Neuroepidemiology 1982;1:176-188. Beghi E, Nicolosi A, Kurland LT, Mulder DW, Hauser WA, Shuster L. Encephalitis and aseptic meningitis, Olmsted County, Minnesota, 1950-1981. I. Epidemiology . Annals of Neurology 1984; 16:283-294.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Beghi E, Kurland LT, Mulder DW, Nicolosi A. Brachial plexus neuropathy in the population of Rochester, Minnesota, 1970-1981. Annals of Neurology 1985; 18:320-323. Bellman MH, Ross EM, Miller DL. Infantile spasms and pertussis immunization. Lancet 1983;1:1031-1034. Bensasson M, Lanoe R, Assan R. Un cas de syndrome algodystrophique du membre superieur survenu apres vaccination antitetanique. [A case of algodystrophy of the upper limb occurring after tetanus vaccination.] Semaine des Hopitaux de Paris 1977;53:2965-2966. Bergey GK, Bigalke H, Nelson PG. Differential effects of tetanus toxin on inhibitory and excitatory synaptic transmission in mammalian spinal cord neurons in culture: a presynaptic locus of action for tetanus toxin. Journal of Neurophysiology 1987;57:121-131. Bilyk MA, Dubchik GK. Anafilakticheskaia reaktsiia posle podkozhnogo vvedeniia stolbmiachnogo anatoksina. [Anaphylactic reaction following subcutaneous administration of tetanus anatoxin.] Klinicheskaia Meditsina 1978;56:137-138. Bjorkholm B, Bottiger M, Christenson B. Antitoxin antibody levels and the outcome of illness during an outbreak of diphtheria among alcoholics. Scandinavian Journal of Infectious Diseases 1986;18:235-239. Burmstein GI, Kreithen H. Peripheral neuropathy following tetanus toxoid administration. Journal of the American Medical Association 1966;198:1030-1031. Burmester GR, Altstidl U, Kalden JR. Stimulatory response towards the 65-kDa heat shock protein and other mycobacterial antigens in patients with rheumatoid arthritis. Journal of Rheumatology 1991;18:171-176. Chanukoglu A, Fried D, Gotlieb A. [Anaphylactic shock due to tetanus toxoid]. Harefuh 1975; 89:456-457. Christensen PE. Side reactions to tetanus toxoid. Scientific Publication, Pan American Health Organization 1972;253:36-43. Christenson B, Bottiger M. Serological immunity to diphtheria in Sweden in 1978 and 1984. Scandinavian Journal of Infectious Diseases 1986;18:227-233. Cody CL, Baraft LJ, Cherry JD, Marcy SM, Manclark CR. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 1981;68:650-660. Cogne M, Ballet JJ, Schmitt C, Bizzine B. Total and IgE antibody levels following booster immunization with aluminum absorbed and nonabsorbed tetanus toxoid in humans. Annals of Allergy 1985;54:148-151. Collier LH, Polakoff S, Mortimer J. Reactions and antibody responses to reinforcing doses of adsorbed and plain tetanus vaccines. Lancet 1979;1:1364-1368. Combes MA, Clark WK. Sciatic nerve injury following intragluteal injection: pathogenesis and prevention. American Journal of Diseases in Children 1960;100:579. Crovari P, Gasparini R, D'Aste E, Culotta C, Romano L. Studio caso-controllo sulla associazione tra sindromi neurologiche e vaccinazioni obbligatorie in Liguria nel periodo Gennaio 1980-Febbraio 1983. [Case-control study on the association of neurological syndromes and compulsory vaccinations in Liguria during the period January 1980-February 1983.] Bollettino dell Istituto Sieroterapico Milanese 1984;63:118-124. Daschbach RJ. Serum sickness and tetanus immunization (letter). Journal of the American Medical Association 1972;220:1619. Deliyannakis E. Peripheral nerve and root disturbances following active immunization against smallpox and tetanus. Military Medicine 1971;136:458-462. Desai BV, Dixit S, Pope RM. Limited proliferative response to type II collagen in rheumatoid arthritis. Journal of Rheumatology 1989;16:1310-1314. Devey ME, Bleasdale K, Isenberg DA. Antibody affinity and IgG subclass of responses to tetanus toxoid in patients with rheumatoid arthritis and systemic lupus erythematosus. Clinical Experimental Immunology 1987;68:562-569.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Griffith RD, Miller OF III. Erythema multiforme following diphtheria and tetanus toxoid vaccination. Journal of the American Academy of Dermatology 1988;19:758-759. Hankey GJ. Guillain-Barré syndrome in Western Australia, 1980-1985. Medical Journal of Australia 1987;146:130-133. Harrer G, Melnizky U, Wendt H. Akkommodationsparese und Schlucklahmung nach Tetanus Toxoid-Auffrischungsimpfung. [Accommodation paresis and swallowing paralysis following tetanus toxoid booster inoculation.] Wien Medizinische Wochenschrift 1971;121:296-297. Herman JH, Bradley J, Ziff M, Smiley JD. Response of the rheumatoid synovial membrane to exogenous immunization. Journal of Clinical Investigation 1971;50:266-273. Hirtz DG, Nelson KB, Ellenberg JH. Seizures following childhood immunizations. Journal of Pediatrics 1983;102:14-18. Holden JM, Strang DU. Reactions to tetanus toxoid: comparison of fluid and adsorbed toxoids . New Zealand Medical Journal 1965;64:574-577. Holliday PL, Bauer RB. Polyradiculoneuritis secondary to immunization with tetanus and diphtheria toxoids. Archives of Neurology 1983;40:56-57. Holmes WH. Diphtheria: History. Bacillary and Rickettsial Infections. New York: Macmillan; 1940. Hopf HC. Guillain-Barré-Syndrom nach Tetanus-Schutzimpfung: Ubersicht und Fallmitteilung. [Guillain-Barré syndrome following tetanus toxoid administration: survey and report of a case.] Aktuelle Neurologie 1980;7:195-200. Höyeraal HM, Mellbye OJ. Humoral immunity in juvenile rheumatoid arthritis. Annals of Rheumatic Disease 1974;33:248-253. Illis LS, Taylor FM. Neurological and electroencephalographic sequel of tetanus. Lancet 1971;1:826-830. Institute of Medicine. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: National Academy Press; 1991. Jacobs RL, Lowe RS, Lanier BQ. Adverse reactions to tetanus toxoid. Journal of the American Medical Association 1982;247:40-42. James G, Longshore WA, Hendry JL. Diphtheria immunization studies of students in an urban high school. American Journal of Hygiene 1951;53:178-201. Jawad AS, Scott DG. Immunization triggering rheumatoid arthritis? (letter). Annals of Rheumatic Disease 1989;48:174. Johnson RT, Griffin DE, Gendelman HE. Postinfectious encephalomyelitis. Seminars in Neurology 1985;5:180-190. Jones AE, Melville-Smith M, Watkins J. Adverse reactions in adolescents to reinforcing doses of plain and adsorbed tetanus vaccines. Community Medicine 1985;7:99-106. Karzon D, Edwards K. Diphtheria outbreaks in immunized populations. New England Journal of Medicine 1988;318:41-43. Kellaway P, Krachoby RA, Frost JD, Zion T. Precise characterization and quantification of infantile spasms. Annals of Neurology 1979;6:214-218. Kittler FJ, Smith PJ, Hefley BF, Cazort AG. Reactions to tetanus toxoid. Southern Medical Journal 1966;59:149-153. Kiwit JC. Neuralgic amyotrophy after administration of tetanus toxoid. Journal of Neurology, Neurosurgery and Psychiatry 1984;47:320. Korger G, Quast U, Dechert G. Tetanusimpfung: Vertraglichkeit und Vermeidung von Nebenreaktionen. [Tetanus vaccination: tolerance and avoidance of adverse reactions.] Klinische Wochenschrift 1986;64:767-775. Kovalskaya SI. Anafilaktogennye svoistva adsorbipovannoi i neadsorbirovannoi kokliusnodifterinostolbniachnoi vaktsin. [The anaphylactogenic properties of absorbed and nonabsorbed

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality pertussis-diphtheria-tetanus vaccines.] Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii 1967;44:105-109. Kuhns WJ, Pappenheimer AM. Immunochemical studies of antitoxin produced in normal and allergic individuals hyperimmunized with diphtheria toxoid. Journal of Experimental Medicine 1952:95:363-374, 375-392. Langholz E, Nielsen OH. Induction of endogenous arachidonic acid metabolism in human neutrophils with snake venom phospholipase A2, immune complexes, and A23187. Prosraglandins, Leukotrienes and Essential Fatty Acids 1990;39:227-229. Leung A. Anaphylaxis to tetanus toxoid. Irish Medical Journal 1984a;77:306. Leung AK. Erythema multiforme following DPT vaccination. Journal of the Royal Society of Medicine 1984b;77:1066-1067. Leung AK, Szabo TF. Erythema multiforme following diphtheria-pertussis-tetanus vaccination. Kobe Journal of Medical Science 1987;33:121-124. Levine L, Edsall G. Tetanus toxoid: what determines reaction proneness? Journal of Infectious Diseases 1981;144:376. Levine L, Ibsen J, McComb JA. Adult immunization: preparation and evaluation of combined fluid tetanus and diphtheria toxoids for adult use. American Journal of Hygiene 1961;73:20-35. Ling CM, Loong SC. Injection injury of the radial nerve. Injury 1976;8:60-62. Lleonart-Bellfill R, Cistero-Bahima A, Cerda-Trias MT, Olive-Perez A. Tetanus toxoid anaphylaxis. DICP Annals of Pharmacotherapy 1991;25:870. Mandal GS, Mukhopadhyay M, Bhattacharya AR. Adverse reactions following tetanus toxoid injection. Journal of the Indian Medical Association 1980;74:35-37. Mansfield LE, Ting S, Rawls DO, Frederick R. Systemic reactions during cutaneous testing for tetanus toxoid hypersensitivity. Annals of Allergy 1986;757:135-137. McComb J, Levine L. Adult immunization. II. Dosage reduction as a solution to increasing reactions to tetanus toxoid. New England Journal of Medicine 1961:265:1152. Miadonna A. Caratteristiche biologiche delle IgE specifiche per il tossoide tetanico. [Biological characteristics of specific IgE for tetanus toxoid.] Bollettino del Istituto Sieroterapico Milanese 1980;59:554-559. Miadonna A, Falagiani P. Determinazione delle IgE specifiche in 15 soggetti con sospetra allergia al tossoide tetanico. [Specific IgE determination in 15 subjects with suspected tetanus toxoid allergy.] Folia Allergologica Immunologica Clinica 1978;25:609-611. Middaugh JP. Side effects of diphtheria-tetanus toxoid in adults. American Journal of Public Health 1979:69:246-249. Miller HG, Stanton JB. Neurological sequel of prophylactic inoculation. Quarterly Journal of Medicine 1954;23:1-27. Mortimer EA. Diphtheria toxoid. In: Plotkin SA, Mortimer EA, eds. Vaccines. Philadelphia: W.B. Saunders: 1988. Mortimer J, Melville-Smith M, Sheffield F. Diphtheria vaccine for adults. Lancet 1986:2:1182-1183. Myers MG, Beckman CW, Vosdingh RA, Hankins WA. Primary immunization with tetanus and diphtheria toxoids: reaction rates and immunogenicity in older children and adults . Journal of the American Medical Association 1982;248:2478-2480. Nagel J, Svec D, Waters T, Fireman P. IgE synthesis in man. I. Development of specific IgE antibodies after immunization with tetanus diphtheria (TD) toxoids. Journal of Immunology 1977;118:334-341. Newton NJ, Janati A. Guillain-Barré syndrome after vaccination with purified tetanus toxoid. Southern Medical Journal 1987:80:1053-1054. Nicolosi A, Hauser WA, Beghi E, Kurland LT. Epidemiology of central nervous system infections in Olmsted County. Minnesota, 1950-1981. Journal of Infectious Diseases 1986; 154:399-408.

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