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Institute of Medicine (US) Vaccine Safety Committee; Stratton KR, Howe CJ, Johnston RB Jr., editors. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington (DC): National Academies Press (US); 1994.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality.

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5Diphtheria 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 protective 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 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 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 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 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.

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.

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 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 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 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.

Conclusion

The evidence favors rejection of a causal relation between DT, Td, or tetanus toxoid and encephalopathy (acute or chronic).

Residual Seizure Disorder

Clinical Description

Seizures are neurologic events that may occur with or without the loss of consciousness and can include a variety of sensory experiences (e.g., auditory seizures), motor manifestations (e.g., focal motor or tonic-clonic seizures), or both. In addition, seizures can occur with or without fever. Febrile seizures are well-defined, relatively common events that are precipitated by fever in children without a seizure disorder. Afebrile seizures are those that occur in the absence of fever. Recurrent afebrile seizures are referred to as epilepsy and are synonymous with residual seizure disorder. Approximately 0.5 to 2 percent of the population experiences epilepsy. It can occur at any age. Infantile spasms are a type of epileptic disorder in young children characterized by flexor, extensor, and mixed flexor-extensor seizures that tend to occur in clusters or flurries (Kellaway et al., 1979). The earliest manifestations of infantile spasms are subtle and are easily missed, making it difficult to identify the precise age at onset. Incidence rates of infantile spasms range from 0.25 to 0.4 per 1,000 live births. The vast majority of studies report a peak onset between ages 4 and 6 months. Approximately 65 percent of children with infantile spasms go on to have other types of seizures. For a more complete discussion of the definition of seizures, see Chapter 3.

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 associated with CNS disease. Tetanus is a neurologic disease characterized by severe muscle spasms produced by the potent neurotoxin tetanospasmin (Wassilak and Orenstein, 1988). This neurotoxin can produce three clinical syndromes: (1) localized, (2) generalized (80 percent of cases), and (3) cephalic. In patients with generalized tetanus, the neurotoxin makes its way to the CNS and can then cause spasm of any muscle as well as autonomic nervous system disturbances. Tetanospasms (generalized tonic-tetanic seizure-like activity) can occur, but cognitive functions are not affected. Tetanospasms are generalized muscle spasms, not generalized seizures in which the level of consciousness is affected. Cephalic tetanus is rare and is associated with cranial nerve palsies. Therefore, clinical diphtheria disease and tetanus disease have not been associated with seizures.

Inasmuch as DT, Td, tetanus toxoid, and DPT have been known to cause fever, they have been associated with the occurrence of acute febrile seizures. Febrile seizures alone do not lead to a residual seizure disorder. There are a paucity of case reports in the literature describing seizures (other than febrile) that have occurred in association with diphtheria and tetanus toxoids. However, several large epidemiologic studies were designed to investigate the association between receipt of DPT and acute neurologic events in children. From those studies, information regarding DT was also obtained because there was not universal acceptance of DPT. Bellman et al. (1983) examined a subset of the NCES data for a relation between the onset of infantile spasms and recent vaccination with DT and DPT. Pollock et al. (1984, 1985) and Pollock and Morris (1983) examined the relation between the onset of neurologic events (including seizures) and vaccination with DT and DPT in several different studies.

Evidence for Association

Biologic Plausibility

There are no data directly bearing on the biologic plausibility of a relation between diphtheria or tetanus toxoid and residual seizure disorder.

Case Reports, Case Series, and Uncontrolled Observational Studies

Three uncontrolled observational (cohort) studies provide descriptive information. The North West Thames study (Pollock and Morris, 1983 [see previous section on encephalopathy]), an uncontrolled cohort study, also offers some information regarding seizures following DT immunization. In the voluntary reporting part of the study, of 133,500 children who received a primary series of three immunizations (400,500 doses) of DT (and OPV), and 221,000 single booster doses of DT given at school entry, seven children had seizures, and all were normal on follow-up. Two of these were febrile seizures associated with respiratory illness and possible fever, and three were in children with personal or family histories of seizures. In the hospital activity analysis, of 18,000 children who received a primary series of DT (and OPV) (54,000 doses), 18 children had seizures, all of which were febrile, within 28 days of immunization. Of the children who presented with neurologic disease after DT immunization, two patients with convulsions with focal signs presenting at 22 and 24 days postimmunization, respectively, were reported. Long-term follow-up of these two patients was not presented in the report, but the relatively long period of time between receipt of DT and seizures (22 and 24 days, respectively) makes a causal inference between receipt of the toxoids and the adverse event much less plausible.

In another uncontrolled study (for the purposes of DT immunization), Pollock et al. (1984, 1985) examined the symptoms that were reported to occur after primary immunization with DT and DPT (and OPV). Infants attending the Hertfordshire Area Health Authority, England, were recruited during a 3-year period beginning in January 1978. They were followed through their primary immunization series, and parents were questioned within 2 weeks and again at 6-8 weeks after each immunization. Of 4,024 children administered 10,601 doses of DT, seizures were reported in 2 children at the first follow-up. One child had a febrile seizure 8 hours after injection of DT, and the other child had a respiratory infection and seizure 5 days after injection of DT. The latter child's sibling had a history of febrile seizures. Neither of these children had residual sequelae. At the 6-week follow-up, three cases of febrile convulsions were reported to have occurred 3-6 weeks postvaccination in three children who received DT but who did not have a personal or family history of seizures, and a fourth case of febrile convulsions was reported in a child with a previous history of convulsions. Neurologic disorders were diagnosed as arising between the first and second follow-up examinations in three children in the group that received DT. Epilepsy was diagnosed in two children; one child had a seizure 8 days after immunization, and another child had a seizure 6 weeks after immunization. The third child had a convulsion and then transitory hemiplegia 5 weeks after immunization. Two of the three children and a sibling of the third child had a prior history of convulsions, therefore implying prior neurologic illness. That study did not show any evidence for residual seizure disorder de novo following receipt of DT.

Hirtz and colleagues (1983) described the results of the National Collaborative Perinatal Project (NCPP), which followed the children born to 54,000 women in 1959 until 1966, when the children were 7 years of age. Medical histories of neurologic events (including seizures) were obtained at regular intervals, and developmental examinations were done at certain intervals. Thirty-nine children in the study experienced a seizure within 2 weeks of immunization (DPT, polio, measles, influenza, smallpox, tetanus booster, or unspecified). All but one of the seizures were febrile. Three children experienced seizures with a latency of longer than 2 weeks following vaccination. One child received DPT, but the vaccines administered to the other two children were not specified. One of those children had a seizure 1 day after receiving a tetanus booster. The child had a prior neurologic history, in that several months earlier he had sustained a skull fracture in a car accident and had been in a coma but had apparently recovered. The data do not make clear whether this child had a febrile seizure or if he had a residual seizure disorder at the 7-year follow-up.

No reports in VAERS submitted between November 1990 and July 1992 describe residual seizure disorders in association with receipt of tetanus toxoid alone, DT or Td alone, or tetanus toxoid, DT, or Td in combination with other vaccines.

Controlled Observational Studies

The most methodologically sound of the observational studies is the case-control study by Bellman et al. (1983), which examined a subset of the NCES data (Alderslade et al., 1981) for the relation between the onset of infantile spasms and recent DT or DPT immunization. They analyzed all 1,182 cases in the NCES (as opposed to the first 1,000, as was done in the larger NCES study [Alderslade et al., 1981]). Cases and controls were compared for their exposure to either DPT or DT in the 7 or 28 days before the onset of spasms. Of the 269 cases of infantile spasms reported to the NCES, there were 19 cases of infantile spasms whose onset was within 28 days of DT immunization. Infantile spasms were positively associated with receipt of DT within the week prior to the date of onset, but were negatively associated with receipt of DT between 1 and 4 weeks prior to the date of onset. The OR for all cases of infantile spasms with exposure to DT within the 28 days prior to the onset of this condition was 0.83 (95 percent CI, 0.46-1.50). This provides strong evidence suggesting that DT does not cause infantile spasms. The authors concluded that DT does not cause the development of infantile spasms but may trigger their onset in those children in whom the disorder is destined to develop.

Controlled Clinical Trials

None.

Causality Argument

There is no demonstrated plausibility that diphtheria or tetanus toxoids can cause residual seizure disorder. The case reports available for review are those in VAERS. No reports in VAERS described seizures after receipt of tetanus toxoid, DT, or Td alone or in combination with other vaccines. There are VAERS reports of seizures in patients following receipt of DPT. Because in these cases DT was given with pertussis vaccine (as DPT) and other vaccines, it is impossible to know which, if any, of the cases of seizures could be attributed to vaccine.

One case-control study (Bellman et al., 1983) examined the question of a possible relation between DT immunization and seizures. Bellman et al. (1983) examined a subset of the NCES data for the relation between the onset of infantile spasms and recent DT and DPT immunizations. Infantile spasms were positively associated with receipt of DT within the week prior to the date of onset but were negatively associated with receipt of DT between 1 and 4 weeks prior to the onset. The unmatched OR for all patients with infantile spasms who were exposed to DT within the 28 days prior to the onset of this condition was 0.83 (95 percent CI, 0.46-1.50). This provides strong evidence suggesting that DT does not cause infantile spasms.

The other studies in the literature that addressed this issue were uncontrolled observational studies. In the North West Thames study (Pollock and Morris, 1983), only two seizures (other than febrile seizures) were reported in association with DT immunization. These cases were found in the hospital activity analysis (case review) part of the study. Two patients with seizures with focal signs presented at 22 and 24 days, respectively, after DT immunization. Long-term follow-up of these patients was not described in the report; therefore, no information describing whether a residual seizure disorder developed was provided. However, the relatively long period of time between the receipt of DT and the development of seizures in both patients (22 and 24 days) makes a causal relation between vaccine and the event much less biologically plausible. In other uncontrolled observational studies by Pollock et al. (1984, 1985), no evidence of residual seizure disorder in association with DT was seen in children who were neurologically normal prior to immunization with DT. In the NCPP uncontrolled cohort study by Hirtz et al. (1983), no cases of residual seizure disorder were seen in association with immunization with tetanus toxoid. The one seizure recorded in temporal association with tetanus toxoid administration occurred in a child with a previous neurologic condition; the data do not make it clear whether he had residual seizure disorder.

Conclusion

The evidence favors rejection of a causal relation between DT and infantile spasms.

The evidence is inadequate to accept or reject a causal relation between DT and residual seizure disorder other than infantile spasms.

The evidence is inadequate to accept or reject a causal relation between tetanus toxoid or Td and residual seizure disorder.

Demyelinating Diseases of the Central Nervous System

Clinical Description

Demyelinating diseases of the CNS can be categorized into disseminated and focal lesions. Acute disseminated encephalomyelitis (ADEM) is characterized by acute depression of consciousness and multifocal neurologic findings occurring within days to weeks (5 days to 6 weeks) following an inciting event. It is characterized pathologically by diffuse foci of perivenular inflammation and demyelination most prominent in the white matter of the brain and spinal cord (Johnson et al., 1985). Optic neuritis and transverse myelitis are focal demyelinating lesions that can occur in isolation or as components of diffuse demyelinating diseases such as ADEM and multiple sclerosis. Transverse myelitis is characterized by the acute onset of signs of spinal cord disease, usually involving the descending motor tracts and the ascending sensory fibers, suggesting a lesion at one level of the spinal cord. The annual incidence of transverse myelitis in Rochester, Minnesota, from 1970 to 1980 was 7.4 per 100,000 individuals (Beghi et al., 1982). Optic neuritis represents a lesion in the optic nerve behind the orbit but anterior to the optic chiasm. No population-based incidence rates were identified. For a more complete description of demyelinating diseases of the CNS, see Chapter 3.

History of Suspected Association

Demyelinating disease of the CNS has long been known to follow viral and some bacterial infections and the administration of live attenuated and inactivated antiviral vaccines. Demyelinating complications following vaccination were first noted after the introduction of rabies vaccine grown in animal brain or spinal cord in the 1880s. On rare occasions, encephalomyelitis also complicated the injection of vaccinia virus, which is used for the prevention of smallpox. For a more complete discussion of the history of the suspected association between vaccines and the development of demyelinating lesions of the CSF, see Chapter 3. In the more recent literature, several case reports of ADEM in association with tetanus toxoid have been described (Schlenska, 1977; Schwarz et al., 1988), but there has not been a pathologically proven case of ADEM following administration of tetanus toxoid, DT, DPT, or Td. Case reports of transverse myelitis (Read et al., 1992; Whittle and Roberton, 1977) and optic neuritis (Quast et al., 1979; Topaloglu et al., 1992) have been presented in the literature as well.

Evidence for Association

Biologic Plausibility

Chapter 3 provided a detailed discussion of the historic and scientific evidence that establishes a relation between vaccines and the development of demyelinating diseases of the CNS. In summary, it is biologically plausible that injection of an inactivated virus, bacterium, or live attenuated virus might induce an autoimmune response in the susceptible host, either by deregulation of the immune response, by nonspecific activation of T cells directed against myelin proteins, or by autoimmunity triggered by sequence similarities to host proteins such as those of myelin. The latter mechanism might evoke a response to a self-antigen (molecular mimicry) (Fujinami and Oldstone, 1989).

Case Reports, Case Series. and Uncontrolled Observational Studies

Reports in the literature of cases that clinically resemble ADEM include one described by Schlenska (1977). A 36-year-old woman developed lethargy, slurred speech, nystagmus, hemihypesthesia, decreased sensation along several thoracic dermatomes, and pyramidal tract signs 5 days after receiving a tetanus toxoid booster. She had good recovery over an 11-month period with no further episodes. Another report by Schwarz et al. (1988) describes a 21-year-old man who developed coma with midbrain signs after tetanus toxoid administration on two occasions 2.5 years apart. Latencies from the time of toxoid administration to the onset of symptoms were 7 and 8 days, respectively.

Several case reports describing transverse myelitis after tetanus booster administration were found in the literature. In 1977, Whittle and Roberton described a 7-month-old girl who developed flaccid paraparesis 6 days after receiving DT and OPV. Read et al. (1992) described a 50-year-old man who developed flaccid legs, areflexia, and a sensory level at T-6 12 days after receiving a tetanus booster. A magnetic resonance imaging study showed no lesions in the brain, suggesting that this lesion was indeed limited to the spinal cord. In a case described by Topaloglu et al. (1992), an 11-year-old girl developed spastic paraparesis, bilateral papillitis, and visual defects 3 days after receiving a booster of tetanus toxoid. An 11-month follow-up showed no recurrence of symptoms, and there was total recovery except for the persistence of pale optic disks. This does suggest disease in multiple foci, as is seen in ADEM, but the time interval between immunization and disease was too brief to suggest a mechanism analogous to experimental allergic encephalomyelitis. Two pertinent case reports of transverse myelitis were found in VAERS (submitted between November 1990 and July 1992). In one patient transverse myelitis developed after administration of Td, and in another patient transverse myelitis developed after administration of Td and hepatitis B vaccine. The temporal and clinical details provided in these reports from VAERS are insufficient for proper evaluation of the cases.

Well-documented cases of optic neuritis following vaccine administration are even rarer than cases of transverse myelitis. Quast et al. (1979) reported a 46-year-old man who developed acute optic neuritis 10 days after receiving a tetanus booster. As discussed above, Topaloglu et al. (1992) described an 11-year-old girl who developed transverse myelitis and optic neuritis 3 days after receipt of a tetanus booster. No cases of solitary optic neuritis in association with tetanus toxoid, DT, or Td were found in VAERS (submitted between November 1990 and July 1992).

Controlled Observational Studies

None.

Controlled Clinical Trials

None.

Causality Argument

There is biologic plausibility for a causal relation between vaccines and demyelinating disorders. The reports in the literature that describe a possible association between demyelinating diseases of the CNS (ADEM, transverse myelitis, and optic neuritis) are case reports. There are at least two case reports in the literature for each of the above-mentioned demyelinating diseases of the CNS. The case reports describe the demyelinating disease that occurs within the biologically plausible latency period of 5 days to 6 weeks, and the case reports provide enough clinical detail that one can be relatively certain of the neurologic diagnosis. What the case reports cannot address is whether the frequency of the cases that occurred was greater than the expected background rate for these specific demyelinating diseases. Annual incidence rates have been estimated for transverse myelitis (Beghi et al., 1982). These data were calculated for Rochester, Minnesota, for the years 1970 to 1980. The estimated rate of 0.83 per 100,000 individuals is much higher than a rate calculated for Israel, presumably because of differences in hove successful the two studies were at identifying all cases of transverse myelitis. No population-based incidence rates for ADEM or optic neuritis were identified. This question is difficult at best for rare adverse events and can be answered only if both good age-specific background rates for the specific disease in question are known and aggressive surveillance of adverse events is carried out or if large controlled observational studies are done. None of this specific information is available when considering the relation between tetanus toxoid, DT, or Td and the occurrence of ADEM, transverse myelitis, or optic neuritis.

Conclusion

The evidence is inadequate to accept or reject a causal relation between tetanus toxoid, DT, or Td and demyelinating diseases of the CNS (ADEM, transverse myelitis, and optic neuritis).

Guillain-Barré Syndrome

Clinical Description

Guillain-Barré syndrome (GBS), also known as acute inflammatory demyelinating polyneuritis, is characterized by the rapid onset of flaccid motor weakness with depression of tendon reflexes and elevation of protein levels in CSF without pleocytosis. The annual incidence of GBS appears to be approximately 1 per 100,000 for adults. The data are not definitive, but the annual incidence of GBS in children under age 5 years appears to be approximately the same. The annual incidence of GBS in children over age 5 years and teenagers appears to be lower. Chapter 3 contains a detailed description of GBS.

History of Suspected Association

Demyelinating disease of the peripheral nervous system has long been known to follow viral and some bacterial infections and can complicate the administration of live attenuated and inactivated viral vaccines. However, vaccinations are an infrequent antecedent event in patients with GBS, probably occurring in less than 1 to 5 percent of all patients. In most large case series of GBS, recent vaccination either is not mentioned or is described in only an occasional person (Hankey, 1987; Winer et al., 1988). For a more complete discussion of the history of the suspected association between vaccines and the development of GBS, see Chapter 3. A number of case reports in the medical literature have described GBS following receipt of tetanus toxoid. These are discussed in the following section.

Evidence for Association

Biologic Plausibility

Chapter 3 provides a detailed discussion of the historical and scientific evidence establishing the biologic plausibility of a relation between vaccines and the development of GBS. In summary, it is biologically plausible that injection of an inactivated virus, bacterium, or live attenuated virus might induce an autoimmune response to peripheral nerve and root in the susceptible host, either by deregulation of the immune response, by nonspecific activation of T cells directed against myelin proteins, or by autoimmunity triggered by sequence similarities to host proteins such as those of myelin. The latter mechanism might evoke a response to a self-antigen, so-called molecular mimicry (Fujinami and Oldstone, 1989).

Case Reports, Case Series, and Uncontrolled Observational Studies

In surveying the medical literature, 29 instances of adverse events labeled as either GBS or polyneuritis were found in association with diphtheria or tetanus toxoids (Dittmann, 1981b; Holliday and Bauer, 1983; Hopf, 1980; Newton and Janati, 1987; Onisawa et al., 1985; Pollard and Selby, 1978; Quast et al., 1979; Reinstein et al., 1982; Robinson, 1981; Rutledge and Snead, 1986; Schlenska, 1977). These occurred primarily in the European literature. The majority of reported cases were in adults who had received either tetanus toxoid alone (21 individuals) or who had received tetanus toxoid and anti-tetanus toxin serum (4 individuals). Anti-tetanus toxin serum is known to induce GBS in its own right (Miller and Stanton, 1954). In most of the case reports describing what was labeled as GBS or polyneuritis, clinical details are lacking or, when present, are inconsistent with the diagnostic criteria for GBS. Three of the 25 cases following receipt of tetanus toxoid are described in enough detail and fall within the diagnostic criteria to be acceptable as documented cases of GBS with an appropriate latency (5 days to 6 weeks) following vaccination (Hopf, 1980; Newton and Janati, 1987; Pollard and Selby, 1978). One patient (Newton and Janati, 1987) received tetanus toxoid made by a U.S.-licensed manufacturer. All these patients were adults.

One particular case reported by Pollard and Selby (1978) is particularly relevant for a possible causal relation between tetanus toxoid and GBS for that case. A 42-year-old male laborer received tetanus toxoid on three separate occasions over a period of 13 years, and following each vaccination a self-limited episode of clear-cut, well-documented polyneuropathy of the GBS variety ensued. The latencies for each episode were 21, 14, and 10 days, respectively. He had minimal residual neurologic signs following the second episode, and made a full functional recovery following the third episode (J. D. Pollard, University of Sydney, Sydney, Australia, personal communication, 1993). A well-studied sural nerve biopsy during the third episode showed demyelination, onion bulb formation, and incipient hypertrophic neuropathy. The patient's lymphocytes could be induced to proliferate upon exposure to tetanus toxoid and to elaborate the lymphokine macrophage inhibition factor upon exposure to peripheral nerve homogenate, although these responses can be seen in vaccinees without GBS. Other studies of hypersensitivity to peripheral nerve antigens were not done. The immunologic basis for his sensitivity to tetanus toxoid was not demonstrated. Subsequently, since 1981, this man has experienced multiple recurrences of demyelinating polyneuropathy, most following acute viral illnesses. Plasmapheresis administered at 3-week intervals was initiated in 1986 and has continued until the time of this writing. In recent years he has remained functionally normal, but has minor residual sensory findings on examination (J. D. Pollard, University of Sydney, Sydney, Australia, personal communication, 1993).

Few cases of GBS following receipt of DT have been reported. Dittmann (1981b) noted that three instances of acute polyneuritis, presumably GBS, were reported as adverse events following administration of this vaccine. These data were based on passive reporting following the distribution of approximately 5.5 million doses of vaccine between 1950 and 1976 in the former East Germany.

The Monitoring System for Adverse Events Following Immunization (MSAEFI) lists four cases of GBS between 1979 and 1990 following vaccination with DT. VAERS lists two cases of GBS in temporal association with Td submitted between November 1990 and July 1992. Both patients simultaneously received DT and MM.

Controlled Observational Studies

None.

Controlled Clinical Trials

None.

Causality Argument

There is biologic plausibility for a causal relation between vaccines and demyelinating disorders. The literature describing a possible association between GBS and tetanus toxoid, DT, or Td consists of case reports. The most convincing case in the literature is that reported by Pollard and Selby (1978), who described a 42-year-old man who developed GBS on three separate occasions (over a 13-year period) following receipt of tetanus toxoid. The relation between tetanus toxoid and GBS is convincing at least for that one individual, even though this man has subsequently experienced multiple recurrences of demyelinating polyneuropathy, most following acute viral illnesses (J. D. Pollard, University of Sydney, Sydney, Australia, personal communication, 1993). Of the other cases relating receipt of tetanus toxoid to the development of GBS, two others (Hopf, 1980; Newton and Janati, 1987) are recorded in enough detail to be accepted as GBS; one of these patients (Newton and Janati, 1987) received tetanus toxoid made by a U.S.-licensed manufacturer. Both patients were adults. Aside from the data in MSAEFI and VAERS, which generally do not provide sufficient clinical descriptions to establish the diagnosis, there is little information in the literature relating DT or Td to the development of GBS. The case series by Dittmann (1981b) describes three cases of polyneuritis following administration of Td. What the case reports cannot address is whether the frequency of cases is higher than the expected background rate of GBS. This question is difficult at best for rare adverse events and can be done only if (1) good age-specific background rates for the specific disease in question are known, (2) aggressive surveillance of adverse events is done, or (3) large controlled observational studies are done. None of this specific information is available when considering the relation between tetanus toxoid, DT, or Td and the occurrence of GBS. However, because the case by Pollard and Selby (1978) demonstrates that tetanus toxoid did cause GBS, in the committee's judgment tetanus toxoid can cause GBS.

Conclusion

The evidence favors a causal relation between tetanus toxoid and GBS.

If the evidence favors a causal relation between tetanus toxoid and GBS, then in the committee's judgment the evidence favors a causal relation between vaccines containing tetanus toxoid (DT and Td) and GBS.

Because the conclusions are not based on controlled studies, no estimate of incidence or relative risk is available. It would seem to be low.

Risk-Modifying Factors

GBS, as a separate discrete attack, recurs in a small percentage of those previously afflicted, perhaps 2 to 3 percent, and some individuals have been known to have three or four separate episodes. Other than the patient described by Pollard and Selby (1978), who experienced three attacks, each within 10-21 days of receipt of tetanus toxoid, cases of recurrence after vaccination are not documented. Nevertheless, if GBS occurs within 5 days to 6 weeks of a vaccination, subsequent vaccinations with either the same or different immunogens could be associated with a greater risk of GBS than if the person had never had GBS. A previous history of GBS unrelated to vaccination as an antecedent event is even more uncertain as a risk factor.

Neuropathy

Clinical Description

The term neuropathy as used here designates those disorders of peripheral nerves other than GBS and has, on occasion, been described in relation to vaccine administration. Most reports fall into two clinical categories, mononeuropathy and brachial neuritis. Diagnosis in both instances rests upon the clinical and electrodiagnostic features. A mononeuropathy implies dysfunction limited to the distribution of a single peripheral nerve large enough to be named. In some instances, mononeuropathy is clearly related to direct injection of vaccine into or near the nerve trunk, as with radial nerve palsy with wrist drop following a misdirected deltoid injection (Ling and Loong, 1976). Brachial neuritis is also known as brachial plexus neuropathy or, in the United Kingdom, as neuralgic amyotrophy. Brachial neuritis is frequently heralded by deep, steady aching pain in the shoulder and upper arm. The annual incidence of brachial neuritis in Rochester, Minnesota, from 1970 to 1981 was 1.64 per 100,000 people (Beghi et al., 1985). For a more complete description, see Chapter 3.

History of Suspected Association

Mononeuropathies, particularly those resulting from direct injection of a substance into the nerve trunk, have been described in the literature in relation to injection of vaccines as well as other therapeutic agents (Ling and Loong, 1976). Brachial neuritis has also been linked to vaccination. A review of brachial neuritis by Tsairis and colleagues (1972) states that about 15 percent of all cases of brachial neuritis occurred following administration of vaccine or antiserum, with tetanus toxoid being the most frequently cited.

Evidence for Association

Biologic Plausibility

Injury of a peripheral nerve by intramuscular injection can result from the needle or injection of the solution into a nerve (Scheinberg and Allensworth, 1957). Nerve damage may also result from chemical irritation and the toxic action of the injected solution (Combes and Clark, 1960; Sunderland, 1968), or neuritis may develop from progressive inflammatory and fibrotic changes (Tarlov et al, 1951). If the injury results from progressive inflammatory and fibrotic changes, there is usually a latent period before the onset of paralysis. The severity of neural damage is determined by the internal structure of the nerve at the site of injury and the amount of toxicity of the injected material (Sunderland, 1968). Most therapeutic agents in use could cause paralysis if injected into the wrong site (Ling and Loong, 1976). The committee did not consider such injuries to be adverse events associated with the toxoid.

The pathogenesis of brachial neuritis is not well understood. It has been suggested that this form of neuropathy may be a manifestation of a systemic or localized infectious disorder, possibly vital, or the result of an allergic or hypersensitivity reaction, such as that which may occur after vaccination, but this is far from conclusive (Tsairis et al., 1972). Although the pathogenesis of brachial neuritis is unclear, it is a well-defined clinical syndrome, and its occurrence following administration of tetanus toxoid has been described in the literature numerous times (Baust et al., 1979; Bensasson et al, 1977; Dittmann, 1981c; Getsbach and Waridel, 1976; Kiwit, 1984; Tsairis et al., 1972).

Case Reports, Case Series, and Uncontrolled Observational Studies

Two case reports in the literature link administration of tetanus toxoid to a peripheral mononeuropathy. Ling and Loong (1976) described a 47-year-old male who developed a left radial nerve palsy 2 weeks following a painful injection of tetanus toxoid into his left arm. This case was felt to be caused by direct injection of tetanus toxoid directly into the radial nerve. Blumstein and Kreithen (1966) described a 23-year-old who developed a complete radial nerve paralysis 7 hours following injection of tetanus toxoid into the right deltoid muscle. Cranial mononeuropathies have been described in three separate case reports. Eicher and Neundorfer (1969) reported a reversible paralysis of the left recurrent laryngeal nerve 8 days after receipt of a booster injection of tetanus toxoid. von Wirth (1965) described a patient who developed reversible deafness resulting from cochlear neuritis 5 days following receipt of a booster of tetanus toxoid. Hatter et al. (1971) described a 21-year-old man who developed deglutition paralysis and accommodation paresis 10 days following receipt of a tetanus toxoid booster. All of these cases, except those in which tetanus toxoid was injected directly into the nerve, were considered to have an allergic basis.

A number of case reports in the literature associate the development of brachial neuritis with administration of tetanus toxoid. Dittmann (1981c) provides an uncritical review of 12 cases of ''neuritis'' following receipt of tetanus toxoid reported in the former East Germany from 1963 to 1976. The average latency was 14 days. Two of the eleven cases that fulfilled all diagnostic criteria of brachial neuritis reported by Beghi and colleagues (1985) listed tetanus toxoid as an antecedant event. One of those two patients also had an antecedent influenzal illness. The latency from vaccination to onset of symptoms was not described for either case. Four separate case reports of brachial plexus neuropathy have also been described (Baust et al., 1979; Bensasson et al., 1977; Gersbach and Waridel, 1976; Kiwit, 1984) in adults (ages 20-48), all following receipt of booster doses of tetanus toxoid, with latencies ranging from 4 days to 3 weeks.

Other cases of probable or unclassified neuropathies are on record as occurring after tetanus toxoid vaccination, sometimes in association with other vaccines (Deliyannakis, 1971; Dieckhoefer et al., 1978; Ehrengut, 1986; Paradiso et al., 1990). The significance of these cases is uncertain.

Three case reports of possible neuropathy following tetanus toxoid or Td administration were found in VAERS (submitted between November 1990 and July 1992). The documentation of the clinical and laboratory findings from these cases is sketchy at best: therefore, the correct diagnosis was difficult to determine. One report described a 47-year-old man who developed a probable brachial neuritis 1 year following receipt of tetanus toxoid. The long latency prior to the onset of symptoms makes this case unlikely to be related to tetanus toxoid. Another report described a 37-year-old man who had pain in his hand immediately after injection of Td into the deltoid muscle; this is probably a case of direct injection into the radial nerve. The last report described a 41-year-old man who developed what was probably brachial neuritis 12 days following receipt of Td.

Tsairis and colleagues (1972) reviewed 99 patients with brachial plexus neuropathy seen at the Mayo Clinic in Rochester, Minnesota, between 1954 and 1968. Of the 99 patients. 14 had immunizations in the month prior to the development of brachial plexus neuropathy (4 patients had received tetanus toxoid alone. 1 had received tetanus toxoid and influenza vaccine, and a 3-month-old had received DPT). Latencies for the group that received tetanus toxoid alone ranged from 6 to 21 days. The authors indicate that some of the affected limbs were contralateral to the injection.

Controlled Observational Studies

None.

Controlled Clinical Trials

None.

Causality Argument

All of the available information in the literature regarding mononeuropathies and brachial neuritis and their relation with tetanus toxoid, DT, or Td come from case reports or uncontrolled observational studies. The evidence found in the literature relating receipt of tetanus toxoid, DT, or Td and mononeuropathy caused by direct injection into the radial nerve comes from two case reports (Ling and Loong, 1976; VAERS). This type of injury is most likely due to the intraneural nature of the injection rather than to some characteristic of the vaccine itself. The committee does not consider this an adverse event related to the vaccine.

The evidence for peripheral mononeuropathy in association with administration of tetanus toxoid, DT, or Td not related to direct injection into the nerve is less clear. Three case reports of transient cranial mononeuropathies that developed 5, 8, and 10 days following administration of tetanus toxoid have been reported in the literature. The authors speculated that these neuropathies were related to a "neuroallergic" phenomenon following injection of tetanus toxoid. Less is known about the etiology or pathogenesis of this type of phenomenon, rendering the evidence for this type of association solely on the basis of three case reports more speculative than conclusive.

Although little is understood regarding the pathogenesis of brachial neuritis as a distinct clinical syndrome, it is well described in the literature. In a large case series a significant portion of the cases were temporally related to vaccine administration, particularly to tetanus toxoid (Tsairis et al., 1972). Likewise, review of individual case reports revealed four well-documented case reports of brachial plexus neuropathy following administration of tetanus toxoid (Baust et al., 1979; Bensasson et al., 1977; Getsbach and Waridel, 1976; Kiwit, 1984), with latencies ranging from 4 to 21 days. Although the mechanisms of brachial neuritis are not well understood, there is biologic plausibility that vaccines could cause an allergic or hypersensitivity reaction that manifests as brachial neuritis. This provides reasonably good, although sparse, evidence that brachial neuritis can occur in relation to tetanus toxoid, although controlled epidemiologic studies designed to look at this relation do not exist.

If one presumes that, on average, the predominantly adult population of Rochester, Minnesota, was receiving tetanus toxoid approximately once every 10 years (120 months) during the periods covered by the Tsairis et al. and Beghi et al. studies, then an "expected" rate of receipt of tetanus toxoid within the month prior to onset of brachial plexus neuropathy can be estimated as 1/120. Based on reported exposure to tetanus toxoid alone in the Tsairis et al. study. the exposure odds ratio (OR) can be roughly estimated as 4.8. For the Beghi et al. study, the corresponding OR is 10.1. Thus the relative risk of brachial plexus neuropathy is on the order of 5 to 10. Given the population-based background incidence reported by Beghi et al. of 1.64 per 100,000 per year, or 0.14 per 100,000 per month, the one-month attributable incidence (excess risk) can be estimated as 0.5 to 1 case per 100,000 tetanus toxoid recipients.

Conclusion

The evidence is inadequate to accept or reject a causal relation between tetanus toxoid, DT, or Td and peripheral mononeuropathy (other than those caused by direct intraneural injection).

The evidence favors acceptance of a causal relation between tetanus toxoid and brachial neuritis.

If the evidence favors acceptance of a causal relation between tetanus toxoid and brachial neuritis, then in the committee's judgment the evidence favors acceptance of a causal relation between DT and Td and brachial neuritis. The relative risk for brachial neuritis following vaccination with tetanus toxoid-containing vaccines can be estimated as on the order of 5 to 10 and the one-month attributable incidence (excess risk) on the order of 0.5 to 1 case per 100,000 tetanus toxoid recipients.

Risk-Modifying Factors

None.

Arthritis

Clinical Description

Arthritis is inflammation of one or more joints detectable as swelling, redness, and tenderness. Arthralgia is pain in a joint or joints. According to the 1988 National Health Interview Survey, approximately 13 percent of respondents surveyed reported currently having "arthritis of any kind or rheumatism." Prevalence rates increased with age, with approximately 0.2 percent of persons under age 18 years reporting arthritis of any kind or arthralgia.

History of Suspected Association

None.

Evidence for Association

Biologic Plausibility

A causal relation between immunization with tetanus or diphtheria toxoid and arthritis is biologically plausible on the basis of the toxoid's potential to induce a systemic form of immune complex disease (serum sickness). However, generalized serum sickness-like reactions require excess circulating antigen, an unlikely occurrence in view of the small amount of protein contained in currently used vaccines. No studies in animals or human subjects suggest an association between tetanus or diphtheria toxoid and arthritis on the basis of any other mechanism.

The immune response to tetanus toxoid is commonly used as a model system to investigate patients suspected of having immunologic abnormalities, either deficiencies of their immune responsiveness or exaggerated, uncontrolled immune responsiveness. Thus, in many studies of diseases thought to be caused by abnormally high inflammatory responses, such as rheumatoid arthritis or systemic lupus erythematosus, the immune responses to tetanus toxoid have been studied in detail. The response to tetanus toxoid also is measured as a control in assessing the response to antigens from infectious agents known to cause disease associated with arthritis in humans (Borrelia species, group A streptococci, and Yersinia species) or in animals (mycobacteria). In patients with these infections, antigens from the infectious agents are suspected of triggering abnormally high responses to self-antigens, such as the components of joint tissue (collagen). Tetanus toxoid is used as a control because most subjects have immunity to this antigen induced by prior immunization. In the extensive literature reporting the results of those studies (Desai et al., 1989; Devey et al., 1987; Herman et al., 1971; Höyeraal and Mellbye, 1974; Yu et al., 1980), no examples of enhanced reactivity specific for tetanus toxoid have been found. Under some experimental conditions, subjects with rheumatoid arthritis had increased reactivities to all antigens to which they had been exposed (Burmester et al., 1991), but when compared with other antigens, tetanus toxoid was also a poor stimulator of synovial cell inflammation (Pope et al., 1989; Söderströn et al., 1990). One study showed that immune complexes containing tetanus toxoid were only weak activators of neutrophils (Langholz and Nielsen, 1990).

Case Reports, Case Series, and Uncontrolled Observational Studies

Jawad and Scott (1989) described a previously healthy 34-year-old woman who developed rheumatoid arthritis following immunization with tetanus toxoid. She received two doses of tetanus toxoid 1 month apart, and 1 week after receipt of the second dose, she developed a severe local reaction at the site of injection that lasted for 10 days. As the local reaction faded, she developed a symmetric inflammatory polyarthritis that persisted and met the clinical and laboratory criteria for rheumatoid arthritis. In a letter to the editor, Daschbach (1972) mentioned a case of what he termed "typical serum sickness" that occurred in a 7-year-old boy 3 days after receipt of an injection of diphtheria and tetanus toxoids. The child responded to treatment with corticosteroids and antihistamines. Serum obtained 6 weeks later had precipitins for tetanus, but none for diphtheria. No further clinical details were given. One case report entitled "Reactive arthritis and immune vasculitis with cardiovascular shock after triple (diphtheria-pertussis-tetanus) vaccination" was found in the literature (Sell and Katzmann, 1990). A 4-month-old infant developed lymphadenopathy, fever, urticaria, and swelling of both wrists within 24 to 28 hours after the initial DPT immunization. All signs of clinical illness resolved in 5 days. The attending physician reported this case in the form of a question to a column in a pediatrics journal. The reply emphasized the importance of attempting to make a scientific determination of the cause of illness. The importance of these efforts became apparent when virologic and serologic tests revealed that the cause of illness was an acute parvovirus type B19 infection. The infant received subsequent DPT immunizations without incident. In a review of the adverse effects of tetanus toxoid that included 740 individuals (Jacobs et al., 1982), no cases of arthritis were reported. Seven persons had arthralgias (1 percent of the reactions). In a review of the experience in the former West Germany with 100 million doses of tetanus toxoid given over 15 years (Korger et al., 1986), 13 of 2,674 adverse events were listed as ''swelling and inflammatory changes of joints." No details or follow-up were provided. Dittmann (1981a,b) reported no cases of arthritis in an extensive review of diphtheria toxoids (DT or diphtheria toxoid alone) covering 15 years in the former East Germany. In a prospective evaluation of reactions to tetanus and diphtheria toxoids carried out in Denmark between 1952 and 1970, no cases of arthritis were reported in association with 2.5 million injections of monovalent tetanus toxoid and 3.7 million injections of combined diphtheria and tetanus toxoids (Christensen, 1972).

No cases of arthritis associated with receipt of tetanus toxoid alone were reported in VAERS (submitted between November 1990 and July 1992). Three cases of arthritis were reported in adults who received Td. In one individual, myalgia, headache, and nausea developed within 1 hour after immunization, and then swelling of multiple joints developed 13 days after receipt of vaccine. The second individual had arthritis (proximal interphalangeal) in one hand that developed immediately after immunization, persisted for 6 weeks, and then resolved. The third patient developed septic arthritis of the left shoulder 6 days after immunization; the septic arthritis was most likely related to the laceration for which tetanus prophylaxis had been given. Seven cases of "joint pain and tenderness radiating to the shoulder with redness and swelling at the site of immunization" after Td immunization were reported on one form. No additional clinical information was provided. One case of erythema multiforme and migratory polyarthritis was reported in a child aged 1.5 years. Symptoms developed 5 days after immunization with Haemophilus influenzae type b (Hib) vaccine, DT, and OPV, but they resolved after 6 weeks; the child also had received acetaminophen. MSAEFI reports from 1979 to 1990 of individuals receiving one vaccine included four reports of joint inflammation (arthralgia or arthritis) following administration of DT. Follow-up was available for two of these individuals, and both recovered. Ninety-nine cases of joint inflammation were reported following Td immunization; of 39 patients available for follow-up, 27 recovered. Two cases of joint inflammation were reported following tetanus toxoid immunization; no follow-up information was available.

Controlled Observational Studies

None.

Controlled Clinical Trials

None.

Causality Argument

The biologic plausibility for a causal relation between diphtheria and tetanus toxoids and arthritis is based on the toxoid's potential to induce serum sickness. Arthritis is fairly common in the nonpediatric population who receives tetanus toxoid or Td. Evidence for an association between diphtheria or tetanus toxoid and arthritis is limited to case reports and case series. The inconclusive nature of the reports of arthritis observed in association with receipt of tetanus and diphtheria toxoids given either alone or in combination provides insufficient evidence for a causal relation. None of the cases included clinical, laboratory, or pathologic evidence for a mechanism of association.

Conclusion

The evidence is inadequate to accept or reject a causal relation between tetanus or diphtheria toxoid and arthritis.

Erythema Multiforme

Clinical Description

Erythema multiforme (EM) is an inflammatory eruption characterized by symmetric erythematous, macular, bullous, papular, nodular, or vesicular lesions of the skin or mucous membranes. The characteristic lesion is an iris (or bull's eye or target) lesion that consists of a central papule with two or more concentric rings. Stevens-Johnson syndrome is a severe form of EM with involvement of at least two mucosal surfaces in addition to the skin eruption. A hypersensitivity reaction to a number of substances, including infectious agents, is a proposed mechanism, but the pathophysiology has not been defined. No population-based incidence rates were identified.

History of Suspected Association

There is no particular history of suspected association between EM and either diphtheria or tetanus toxoid. Two cases of EM following DPT immunization were identified by Leung (1984b). Leung and Szabo (1987) reported two additional cases following administration of DPT in 1987.

Evidence for Association

Biologic Plausibility

In 1980, Shelley produced the classic iris lesions of EM by intradermal injection of a variety of heat-killed bacteria or their common endotoxin, lipopolysaccharide W, into a patient who was recovering from erythema multiforme bullosum of unknown etiology. Biopsy of the lesions induced by injection of bacterial products showed immunoglobulin A (IgA), IgM, fibrin, and complement deposition that duplicated the findings in the patient's spontaneous lesions. In addition, the patient's peripheral leukocytes produced fibrin thrombi in vitro when exposed to gram-negative bacterial antigens and endotoxin. It is biologically plausible that similar bacterial antigens in diphtheria or tetanus toxoid could induce EM.

Case Reports, Case Series, and Uncontrolled Observational Studies

In 1988, Griffith and Miller reported a case of EM following administration of diphtheria and tetanus toxoids. Eight hours after his third immunization with DT and OPV, a 9-month-old infant developed a generalized maculopapular dermatitis that progressed to vesicular lesions after 4 days.

Several were hemorrhagic and some were target-like. Biopsy revealed "a partially necrotic epidermis with subepidermal vesicles, scattered mononuclear infiltrate in the papillary and reticular dermis, and some exocytosis" (p. 758). Those authors stated that, to their knowledge, this was the first case of EM following DT immunization. They reported that they contacted all current and previous manufacturers of diphtheria and tetanus toxoids and could confirm no other cases.

Two cases of EM following Td immunization were reported to VAERS (submitted between November 1990 and July 1992). One case occurred in a woman who was also treated with silver sulfadiazine cream for a burn. The other case occurred in a woman who was allergic to iodine, but no details about the indication for immunization or the use of antiseptics or antibacterial agents for wound care were provided. One case of EM was reported in a child 5 days after she received Hib, DT, OPV, and acetaminophen. This child also had migratory polyarthritis that lasted for 6 weeks, and a diagnosis of serum sickness was made (see section on arthritis above).

Controlled Observational Studies

None.

Controlled Clinical Trials

None.

Causality Argument

There is biologic plausibility for a relation between diphtheria and tetanus toxoids and EM on the basis of a hypersensitivity mechanism and an investigation of bacterial injection in one human subject. The direct evidence in humans for an association between diphtheria or tetanus toxoid and EM is limited to one published case report of EM occurring after the administration of DT and three case reports made to VAERS (two Td, one DT). However, in one of the cases reported to VAERS, the patient had been exposed to another likely cause of EM, and in another, the patient had been immunized with multiple vaccines.

Conclusion

The evidence is inadequate to accept or reject a causal relation between tetanus or diphtheria toxoid and EM.

Anaphylaxis

Clinical Description

Anaphylaxis is a sudden, potentially life-threatening, systemic condition mediated by highly reactive molecules from mast cells and basophils. The clinical manifestations of anaphylaxis include pallor and then diffuse erythema, urticaria, and itching, subcutaneous edema, edema and spasm of the larynx, wheezing, tachycardia, hypotension, and hypovolemic shock, usually occurring within minutes of intramuscular or subcutaneous exposure to antigen. For this review, cases of anaphylaxis occurring within 4 hours of vaccine administration were included (Table 5-1). Chapter 4 contains a more complete discussion of anaphylaxis.

TABLE 5-1. Case Reports of Anaphylaxis Following Vaccination with Diphtheria or Tetanus Toxoid.

TABLE 5-1

Case Reports of Anaphylaxis Following Vaccination with Diphtheria or Tetanus Toxoid.

History of Suspected Association

Induction of active immunity to tetanus in human subjects was first demonstrated in 1927 by Ramon and Zoeller. Widespread use of tetanus toxoid as a vaccine began in 1938, and initially, there were few reports of side effects. However, in 1940, Whittingham reported 12 cases of "constitutional symptoms" and two cases of anaphylaxis occurring after receipt of initial or subsequent doses of vaccine made up of either fluid or alum-precipitated preparations. Parish et al. (1940) reported an additional case of anaphylaxis, and Regamey (1965) reported fatal anaphylaxis in a man immunized in 1933. A probable association between the reactions and beef proteins in the culture broth was demonstrated by scratch testing with Witte peptone, a medium supplement made from beef and pork fibrins (Gold, 1941; Whittingham, 1940). When these components were removed, no further anaphylactic reactions were reported until 1973 (Staak and Wirth, 1973). Since that time, an interval when hundreds of millions of doses have been administered, nine cases of anaphylaxis meeting the definition given above could be found in literature from throughout the world.

Concern over the possibility of serious hypersensitivity reactions in association with diphtheria immunization was raised because of the high rate of local reactivity in adults, the frequent reactions to control toxoid in the Schick test (Kuhns and Pappenheimer, 1952; Pappenheimer, 1984), and the frequent development of IgE antibodies after immunization with tetanus and diphtheria toxoids (Nagel et al., 1977).

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 two injections of Td without difficulty. In that study, the investigators found a much lower rate of severe reactions than the 10 percent reported by Edsall et al. in 1954, but the authors noted that many reacting substances had been eliminated from the toxoid since that time.

Case Reports, Case Series, and Uncontrolled Observational Studies

Thirteen cases of anaphylaxis meeting the criteria of a life-threatening systemic reaction occurring within 4 hours of immunization with tetanus toxoid have been reported in the literature. These cases are summarized in Table 5-1. One of the 13 cases of anaphylaxis from 1933 was described in a review by Regamey (1965). Three occurred in 1940 and were presumed (by skin testing) to be related to contamination of the vaccine by Witte peptones (Parish and Oakley, 1940; Whittingham, 1940). Two deaths occurred in association with tetanus toxoid administered as a single antigen. In the 1965 review, Regamey reported a fatality in a 20-year-old man 2 hours after he received his third tetanus toxoid injection. This patient had a history of an episode of collapse and convulsions after receiving his second dose of tetanus toxoid. In 1973, Staak and Wirth reported the death of a 24-year-old woman 30 minutes after receiving an injection of tetanus toxoid.

The cause of death was thought to be an anaphylactic reaction. Postmortem examination revealed emphysema of the lungs with bronchial hypersecretion and peribronchial infiltration with eosinophils, findings consistent with anaphylaxis. No local reaction was present at the site of injection. The woman had a history of chronic bronchitis and had tolerated previous immunizations with tetanus toxoid well. Her last immunization had occurred 14 years earlier. Two letters to the editor questioning the assumption of causality followed publication of that report. Spiess and Staak (1973) raised the possibility of inadvertent intravascular injection, and Ehrengut and Staak (1973) noted that vaccine was given ''in both arms," raising the issue that equine antiserum might have been given in addition to vaccine. They noted that in the previous report of death following immunization with tetanus toxoid, Regamey (1965) believed the reaction may have been related to the use of blood components from horses during toxoid production (the patient was immunized in 1933). Since the report by Staak and Wirth in 1973, no case report of death following immunization with tetanus toxoid alone has been reported.

One patient with anaphylaxis (Ratliff and Burns-Cox, 1984) received 4 ml of 2 percent lignocaine in addition to tetanus toxoid. The young man reported by Lleonart-Bellfill et al. (1991) received tetanus toxoid and typhoid vaccine simultaneously, but intradermal skin testing with a 1:10 dilution of aluminum-adsorbed tetanus toxoid performed 3 months later elicited an immediate positive wheal reaction, whereas similar testing with typhoid vaccine was negative. Patch testing with thimerosal and aluminum hydrochloride also was negative. The patient had elevated total serum IgE levels, although the authors noted that even the presence of specific anti-tetanus IgE in the serum correlates poorly with severe anaphylaxis because elevated levels of IgE are found in many healthy individuals without a clinical history of hypersensitivity to tetanus toxoid (see above). Four additional patients (Kittler et al., 1966; Leung, 1984a; Mansfield et al., 1986) had features strongly suggestive of anaphylaxis, but they received epinephrine promptly, and thus, the full clinical syndrome may not have developed.

In the report by Korger et al. (1986) concerning data on adverse reactions collected in the former West Germany over 15 years (1970-1984), during which time 100 million doses of tetanus toxoid were dispensed, no cases of anaphylactic shock after receipt of tetanus toxoid were reported.

In 1946, Werne and Garrow reported fatal anaphylactic shock in identical twin infants, aged 10 months, following immunization with their second injection of both diphtheria toxoid and pertussis antigen. It was recorded that the infants cried "considerably" after reaching home, drank large amounts of water, and "fell asleep." Later, they were arousable only by loud noises, and one infant was noted to be "cold and wringing wet with perspiration." The following morning, the infants were taken to the hospital, where one 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 (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.

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.

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.

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