Adverse Effects of Pertussis and Rubella Vaccines (1991) / Chapter Skim
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4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy
4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy
Pages 65-124
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From page 65... ...
The hypsarrhythmic EEG pattern usually disappears with maturation, and ~50 percent of cases may have normal EEGs by age 8 years, although ~65 percent of children with infantile spasms will go on to have other types of seizures (Glaze and Zion, 19851. Descriptive Epidemiology Age-specific incidence rates are not available, although the vast majority of studies report a peak onset between ages 4 and 6 months (Cowan and 65
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From page 66... ...
Incidence rates of infantile spasms range from 0.25 per 1,000 live births in Denmark and the United States to 0.4 per 1,000 live births in Finland (Leviton and Cowan, 1981~. Most investigators divide infantile spasms cases into two categories which are defined on the basis of the presence or absence of a presumed cause and the child's developmental status prior to the onset of spasms.
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From page 67... ...
The time intervals reported between vaccination and the onset of infantile spasms have been from minutes to weeks (Melchior, 1971~. Evidence from Studies in Humans Case Reports and Case Series One of the largest case series of infantile spasms following pertussis immunization was published by Millichap (1987~.
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From page 68... ...
had been immunized within 1 month of the onset of spasms, 10 with DPT or DP vaccine alone, 5 with DPT vaccine in combination with one or more other vaccines, 4 with smallpox vaccine alone, 2 with Japanese encephalitis vaccine alone, and 1 with polio vaccine alone. Of the 15 cases of infantile spasms with onset after immunization with either DPT or DP vaccine alone or DPT vaccine in combination with another vaccine, onset occurred after the first immunization in 3 cases, after the second in 10 cases, and after the third in 2 cases.
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From page 69... ...
Monitoring System for Adverse Events Following Immunization (MSAEFI) system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J.
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From page 70... ...
A similar analysis, also based on data from Denmark, was done by Shields and colleagues (1988~. The study considered the frequencies of epilepsy, febrile seizures, infantile spasms (as a subgroup of all cases of epilepsy)
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From page 71... ...
. For instance, even if 29 percent of all cases of infantile spasms were caused by DPT immunization, the data of Shields and colleagues would have only about a 50 percent chance of finding a significant difference.
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From page 72... ...
Fifty-five cases of first afebrile seizures were identified; two of these children had infantile spasms, but the onset of spasms did not occur within 30 days of DPT immunization in either of them. The authors pointed out that since adrenocorticotropic hormone and steroids were not among the drugs for which pharmacy records were screened, some cases of infantile spasms may have been missed.
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From page 73... ...
However, risks of infantile spasms were higher within the first 7 days following administration of both DPT and DT vaccines than they were for the other three time periods, when there appeared to be a deficit of infantile spasms cases (RRs for the four time periods O to 6, 7 to 13, 14 to 20, and 21 to 28 days were 1.2, 0.6, 0.4, and 0.6, respectively, following DPT immunization and 1.3, 0.7, 0.8, and 0.5, respectively, following DT immunization)
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From page 74... ...
was a large casecontrol investigation of the association between the risk of serious acute necrologic illness and DPT immunization in young children. A detailed description of SONIC is given later in this chapter.
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From page 75... ...
Profoundly handicapped children, defined as those older than age 5 who could neither walk nor talk, were more often observed among the tuberous sclerosis cases with seizures who were immunized after their first seizure (8 of 27~. Of those immunized after their first seizure and for whom the type of immunization was known, the frequency of profound handicap was 6 of 13 who received DT vaccine and 2 of 14 who received DPT vaccine.
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From page 76... ...
The strongest evidence bearing on the question of a relation between DPT immunization and the risk of infantile spasms comes from the controlled studies from Denmark that compared the distributions of ages at the time of onset of infantile spasms under two different immunization schedules and the large case-control study of infantile spasms from the NCES. Comparison of the ages at onset of cases of infantile spasms for two different time periods in Denmark showed nearly identical distributions (Shields et al., 1988~.
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From page 77... ...
Information on infantile spasms may provide a reasonable estimate. History of Suspected Association with Pertussis Vaccines The suspected association between pertussis immunization and hypsarrhythmia probably derives from the case reports of vaccination and infantile spasms.
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From page 78... ...
resident of England, Scotland, or Wales Walker et al., 1988 Matched case-cohort 1972-1983 26,600 members of Group Health Coop erative, Puget Sound Gale et al., 1990 Matched case-control 1987-1988 ~109,000 children aged (SONIC) 1-24 months; resi dent of Washington or Oregon aNCES, National Childhood Encephalopathy Study; SONIC, Study of Neurologic Illness in Children.
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From page 79... ...
9.6 25.4 20 controls C"Power" denotes the probability that a statistical test based on a sample of the same size as the one in the study cited would find a statistically significant increased risk (with alpha = 0.05) , given that the true RR in the population being studied is the number stated in the table.
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From page 80... ...
Each child served as his or her own control, and all second EEGs were done within 16.5 to 48 hours postimmunization. Of the 83 infants, 40 were given alum-precipitated DPT vaccine and 43 received pertussis vaccine alone.
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From page 81... ...
In the population and time interval studied, there appeared to be no temporal trend in the incidence of infantile spasms. Among the 113 cases of infantile spasms admitted to pediatric departments in Denmark (Melchior, 1977)
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From page 82... ...
Conclusion Evidence does not indicate a causal relation between DPT vaccine or the pertussis component of DPT and hypsarrhythmia. ASEPTIC MENINGITIS Clinical Description Aseptic meningitis is defined as inflammation of the meninges characterized by abnormal numbers of leukocytes in the cerebral spinal fluid (CSF)
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From page 83... ...
History of Suspected Association with Pertussis Vaccines The basis for suspecting an association between pertussis vaccination and aseptic meningitis is unclear, but it may have developed, in part, because of the difficulty inherent in identifying a causal agent in cases of viral meningitis. Data from Rochester, Minnesota, for the time period 1950 to 1981 indicate that in the absence of intensive laboratory investigation, evidence of a virus was obtained for only 12 percent of cases of aseptic meningitis (Beghi et al., 19841.
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From page 84... ...
occurring within 28 days of DPT immunization were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990~.
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From page 85... ...
is also not consistent with a causal relation to DPT immunization, since there was no indication that immunizations also clustered during these months. In addition, data from Rochester, Minnesota, suggest that the risk of aseptic meningitis within 1 week of immunization with pertussis vaccine was not increased over the expected frequency (Beghi et al., 1984~.
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From page 86... ...
ENCEPHALOPATHY Clinical Description Before discussing the evidence for an association between pertussis immunization and encephalopathy, it is reasonable to consider what is meant by the term encephalopathy. Encephalopathy has been used in the literature to characterize a constellation of symptoms and signs reflecting a generalized disturbance in brain function.
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From page 87... ...
In addition to the various ways in which seizures may present clinically, they can occur with or without fever. Febrile seizures are well-defined, rela
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From page 88... ...
Afebrile seizures are those that occur in the absence of fever or other acute provocation. Recurrent afebrile seizures are referred to as epilepsy.
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From page 89... ...
have been well described in both preclinical and human investigations (Volpe, 1987~. In theory, pathologic studies of children who have died after an encephalopathy temporally related to the administration of pertussis vaccine could help to clarify the vague clinical picture of encephalopathy in general and encephalopathy associated with pertussis immunization in particular.
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From page 90... ...
Reported prevalence rates of epilepsy, that is, recurrent afebrile seizures, in children tend to range between 4 and 5 per 1,000 (Leviton and Cowan, 1982~.
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From page 91... ...
Despite these early reports, it was the report by Byers and Moll (1948) of encephalopathy following pertussis immunization in 15 children that spurred interest in the possibility of adverse consequences of pertussis immunization.
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From page 92... ...
Stewart (1977) collected a case series of adverse events following administration of pertussis vaccine and following whooping cough from retrospective data obtained from parent organizations, hospital records, physician reports, and parent reports.
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From page 93... ...
followed 46 children who reportedly experienced the first onset of necrologic symptoms within the 72 hours following DPT immunization. No other cause of symptoms was found.
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From page 94... ...
of the 2,531 cases of febrile seizures and 258 (75 percent) of the 344 cases of afebrile seizures/convulsions also received at least one other vaccine at the time of DPT immunization.
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From page 95... ...
In these three studies (excluding the data from Pollock and Morris voluntary reports) , children were evaluated following a total of 51,794 DPT immunizations and 35,385 DT immunizations.
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From page 97... ...
This suggests that events following DPT immunization were preferentially reported and that the results of the study which relied on voluntary reports are unreliable. The systematic review of hospital discharge diagnoses included surveillance of approximately 17,000 children who had received approximately
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From page 98... ...
. There was one child with a transient hemiparesis 36 hours following DPT immunization (possible encephalopathy)
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From page 99... ...
were observed in either group. The National Childhood Encephalopathy Study The NCES was a large, case-control study initiated in 1976 in response to concerns about declining levels of DPT immunization among children in Great Britain (Alderslade et al., 1981~.
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From page 100... ...
80~. The study included 1,182 cases of serious acute neurologic illnesses in infants and children ages 2 to 35 months in England, Scotland, and Wales between July 1976 and June 1979.
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From page 101... ...
As Table 4-3 shows, the tests had 50 percent power for RRs of as low as 2.0. These results suggest that DPT immunization is associated with an increased risk, within 7 days, of seizures and encephalopathy.
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From page 102... ...
to obtain a result that showed no significant association of serious acute necrologic events with DPT immunization It is unlikely that underreporting of this magnitude occurred, since participating physicians were sent cards each month to remind them to report cases, selective review of hospital discharge records as part of the study did not reveal substantial underreporting, the overall incidence rate of encephalopathy (7 per 100,000 children) was similar to that reported by others, and the rates of all serious necrologic disease did not vary markedly within the 16
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From page 103... ...
In a separate analysis of the 37 cases of Reye syndrome, investigators reported that only one of these cases occurred within 7 days of DPT immunization (Bellman, 1983~. Therefore, the effect of including these cases would be negligible.
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From page 104... ...
An analysis with a broad stratification by socioeconomic status found similar relative risks in both strata. Since the authors of the NCES were able to estimate the total number of DPT immunizations given to children in the NCES study population, they were able to calculate an attributable risk, that is, the number of excess cases seen in the population receiving DPT vaccine.
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From page 105... ...
Given the limited information available, especially regarding the methods used to assess and define late dysfunction, the committee was unable to apply the follow-up data of Madge and colleagues to its assessment of the relation of pertussis vaccine to permanent neurologic damage. The analyses relating to permanent neurologic damage have also received intense scrutiny (Griffith, 1989; MacRae, 1988; Marcuse and Wentz, 1990; Miller et al., 1989; Stuart-Smith, 1988; Wentz and Marcuse, 1991~.
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From page 106... ...
, about 10 percent of those with a history of febrile seizures were noted to have a recurrent febrile seizure within 24 hours of initial pertussis immunization (none of whom subsequently developed epilepsy) , and of 284 patients with epilepsy and frequent seizures, a few had a temporary increase in severity or frequency of seizures following pertussis immunization, but no apparent permanent effects were noted (Livingston, 19721.
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From page 107... ...
Estimates of permanent neurologic damage following DPT immunization have been based on data for these seven children, five of whose acute event was classified as encephalopathy and two of whose event was classified as seizure. Although these children were presumed to be normal at the time of immunization, no prevaccine neurologic testing was performed.
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From page 108... ...
Using the period 30 or more days following DPT immunization as the reference period, the authors identified one, one, and four afebrile seizures in the 0 to 3, 4 to 7, and 8 to 29 days after DPT vaccination, respectively, compared with 1.1, 0.9, and 3.1 expected cases, respectively (Table 4-51. The RRs for these periods were 1.0, 1.2, and 1.5, respectively, but none were significantly elevated.
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From page 109... ...
c to 5 8 o o _ o z o z o so 4 o o Cal us EM ~4 1, Ct .
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From page 110... ...
An RR of 2.7 for febrile seizures had 50 percent power and an RR of 4.1 had 80 percent power. This study thus demonstrated no increase in afebrile seizures or encephalopathies in the early postimmunization period.
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From page 111... ...
Only two children with encephalopathy were identified (Table 4-41; the onset of symptoms did not occur within 2 weeks of immunization in either child. There were one, two, one, and three children with afebrile seizures in the intervals 0 to 3, 4 to 7, 8 to 14, and 15 to 29 days, respectively, following DPT immunization compared with 35 in the interval 30 or more days post-DPT vaccination, yielding RR estimates (95 percent CIs given in parentheses)
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From page 112... ...
This study demonstrated no significant increase in febrile seizures in the 0 to 3 days following DPT immunization (RR, 1.5~; however, the upper bound of the 95 percent CI was 3.3. For febrile seizures, the power was greater than those for afebrile seizures and encephalopathy: 50 percent for an RR of 2.2 and 80 percent for an RR of 3.1.
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From page 113... ...
Of these, the onset of illness was within 28 days of a previous DPT vaccination for 48 children and within 7 days of a previous DPT vaccination for 14 children. The odds ratio for the occurrence of any of the necrologic illnesses included in SONIC within 7 days of DPT immunization was 1.2 (95 percent CI = 0.6-2.3~.
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From page 114... ...
CRR (95% CI) , Estimated relative risk (95 percent confidence interval)
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From page 115... ...
, under a random-effects model. Thus, regardless of the kind of statistical model assumed, the pooled data from these three studies indicate an increased relative risk for febrile seizures following DPT immunization.
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From page 116... ...
In summary, it is not evident that the studies in animals completed to date provide information useful to understanding the possible relation of encephalopathy to pertussis immunization in children. Aluminum Salts The possibility has been raised that the aluminum salts regularly present in DPT vaccines might play a role in the occurrence of encephalopathy following DPT immunization (see Appendix E for discussion)
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From page 117... ...
In addition, the total number of children with chronic conditions on which risk estimates were based was very small' and estimates of chronic necrologic damage following specific types of acute illnesses, especially encephalopathy, could not be calculated. The results of studies comparing rates of febrile seizures following DPT versus DT vaccine (Cody et al., 1981; Pollock and Morris, 1983; Pollock et al., 1984)
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From page 118... ...
The committee's conclusions on the relation of these adverse events to DPT immunization are as follows febrile seizures: the evidence indicates a causal relation between DPT vaccine and febrile seizures; afebrile seizures: the evidence does not indicate a causal relation between DPT vaccine and afebrile seizures; epilepsy: there is insufficient evidence to indicate a causal relation between DPT vaccine and epilepsy.
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From page 119... ...
1989. Analyses of adverse reactions to diphtheria and tetanus toxoids and pertussis vaccine by vaccine lot, endotoxin content, pertussis vaccine potency and percentage of mouse weight gain.
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From page 120... ...
1978. Febrile seizures and later intellectual performance.
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From page 121... ...
1955. Reactions from DPT immunization and its relationship to allergic children.
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From page 122... ...
1981. Pertussis immunization and serious acute neurological illness in children.
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From page 123... ...
1987. Etiology and treatment of infantile spasms: current concepts, including the role of DPT immunization.
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From page 124... ...
1988. Neurologic events following diphtheria-tetanus-pertussis immunization.
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