Adverse Events Associated with Childhood Vaccines Evidence Bearing on Causality (1994) / Chapter Skim
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5 Diptheria and Tetanus Toxoids
5 Diptheria and Tetanus Toxoids
Pages 67-117
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From page 67... ...
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.
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From page 68... ...
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)
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From page 69... ...
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)
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From page 70... ...
should be used in children younger than age 7 years in whom DPT is contraindicated. Tetanus and diphtheria toxoids for adult use (Td)
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From page 71... ...
Also, protective immunity was observed in young infants, most likely on the basis of the presence of transplacentally acquired antibody (Schick, 19131. Diphtheria toxoid adsorbed with aluminum hydroxide or phosphate was shown to be more immunogenic and to produce fewer local reactions than fluid toxoid.
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From page 72... ...
reduction of the dose of toxoid (<2 Lf of diphtheria toxoid in Id versus 10-20 Lf in DPT and 1012 Lf in DT)
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From page 73... ...
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.
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From page 74... ...
and therefore do not provide much additional knowledge of the adverse events following immunization with DT. Quast and colleagues (1979)
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From page 75... ...
(Alderslade et al., 1981) , which was undertaken because of concerns about possible adverse events following receipt of pertussis vaccine.
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From page 76... ...
(1984) drew its cases from admissions to the intensive care unit, infectious disease ward, and general ward of the hospital of the Istituto G
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From page 77... ...
If the evidence favors rejection of a causal relation between DT and acute encephalopathy, then in the committee's judgment the evidence favors rejection of a causal relation between DT and chronic encephalopathy and between Td and tetanus toxoid alone and encephalopathy.
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From page 78... ...
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.
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From page 79... ...
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)
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From page 80... ...
That study did not show any evidence for residual seizure disorder de novo following receipt of DT. Hirtz and colleagues (1983)
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From page 81... ...
Controlled Clinical Trials None. Causality Argument There is no demonstrated plausibility that diphtheria or tetanus toxoids can cause residual seizure disorder.
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From page 82... ...
The one seizure recorded in temporal association with tetanus toxoid administration occurred in a child with a previous necrologic 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.
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From page 83... ...
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.
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From page 84... ...
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.
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From page 85... ...
Controlled Clinical Trials None. Causality Argument There is biologic plausibility for a causal relation between vaccines and demyelinating disorders.
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From page 86... ...
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)
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From page 87... ...
The latter mechanism might evoke a response to a self-antigen, socalled 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~.
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From page 88... ...
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.
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From page 89... ...
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)
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From page 90... ...
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.
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From page 91... ...
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; Gersbach 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.
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From page 92... ...
Another report described a 37-yearold 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.
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From page 93... ...
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 welldocumented case reports of brachial plexus neuropathy following administration of tetanus toxoid (Baust et al., 1979; Bensasson et al., 1977; Gersbach and Waridel, 1976; Kiwit, 1984)
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From page 94... ...
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)
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From page 95... ...
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.
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From page 96... ...
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~.
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From page 97... ...
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.
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From page 98... ...
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.
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From page 99... ...
Conclusion The evidence is inadequate to accept or reject a causal relation between tetanus or diphtheria toxoid and EM.
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From page 100... ...
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., 19771.
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From page 101... ...
In a study of 158,230 airmen who received two injections of alumprecipitated 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~.
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From page 102... ...
102 ADVERSE EVENTS ASSOCIATED WITH CHILDHOOD VACCINES TABLE 5-1 Case Reports of Anaphylaxis Following Vaccination with Diphtheria or Tetanus Toxoid Time of First Study; Vaccines Symptom Generalized Generalized (h) Urticaria Pruritis Flush Edema Collapse Whittingham, 1940; tetanus No Yes Yes Yes Yes Whittingham, 1940; 0.1 Yes Yes Yes Yes No tetanus Parish and Oakley, 1940; tetanus 0.1 Yes Yes Yes No Yes Regamey, 1965; 2 ?
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From page 103... ...
DIPHTHERIA AND TETANUS TOXOIDS 103 Hypotension Wheezing Upper Airway Obstruction Other Epinephrine Analphylaxis ? Dyspnea ?
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From page 104... ...
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.
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From page 105... ...
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.
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From page 106... ...
, 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.
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From page 107... ...
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.
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From page 108... ...
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.
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From page 109... ...
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.
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From page 110... ...
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.
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From page 111... ...
Infantile spasms and pertussis immunization. Lancet 1983;1:10311034.
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From page 112... ...
[Neural complications following immunization against diphtheria.] Deutsche Medizinische Wochenschrift 1986;111:939-942.
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From page 113... ...
Holliday PL, Bauer RB. Polyradiculoneuritis secondary to immunization with tetanus and diphtheria toxoids.
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From page 114... ...
Primary immunization with tetanus and diphtheria toxoids: reaction rates and immunogenicity in older children and adults. Journal of the American Medical Association 1982;248:2478-2480.
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From page 115... ...
Lawrence HS, Banton JJ. A study of reactions following administration of crude and purified diphtheria toxoid in an adult population.
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From page 116... ...
Diphtheria and tetanus toxoids. British Medical Bulletin 1969;25:177-182.
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From page 117... ...
Transverse myelitis after diphtheria, tetanus, and polio immunisation. British Medical Journal 1977; 1:1450.
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