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DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis member had served on the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines, the Vaccine Safety Committee, or both. The committee held a half-day session that was open to observation by invited members of the U.S. Public Health Service and to representatives of advocacy groups. During this session, the committee heard presentations about the new findings of the NCES. The speakers were Dr. David Miller, a key investigator of the NCES, and Dr. Gerald Golden, a pediatric neurologist. Dr. John Menkes, another pediatric neurologist, was invited to speak but was unable to attend and so submitted his comments in writing. The committee questioned the speakers at length. The committee conducted its final deliberations in executive session. The committee adopted a position of neutrality as they started considering and assessing the data, presuming neither the presence nor the absence of a causal relation. The committee used the five categories of conclusions used by the two previous committees, and followed the terminology of the Committee to Study the Adverse Consequences of Pertussis and Rubella Vaccines (IOM, 1991). (See Table 1 for comparisons of the two committees' terminologies.) The strength of evidence required of each category is the same across studies, even though the wording is different. These requirements are discussed in the committees ' reports (IOM, 1991, 1994). EVIDENCE BEARING ON CAUSALITY The National Childhood Encephalopathy Study—1981 The NCES was a case-control study of serious acute neurologic illnesses in children in Great Britain (Alderslade et al., 1981; Miller et al., 1981). Case patients were enrolled in the NCES between 1976 and 1979 and were between the ages of 2 and 35 months. All pediatric, infectious disease, and neurosurgical consultants in England, Scotland, and Wales were asked to notify the study authors about all children admitted to a hospital with specific diagnoses of: acute or subacute encephalitis, encephalomyelitis, and encephalopathy (including postinfectious encephalitis (but not pyogenic infections) and where encephalitis was used to indicate any infective or inflammatory cerebral disorder and where encephalopathy was used when the cause of the cerebral disorder was not immediately obvious); unexplained loss of consciousness; Reye syndrome; convulsions with a total duration of more than half an hour, or followed by coma lasting 2 hours or more, or followed by paralysis or other neurologic signs not previously present and lasting 24 hours or more; or infantile spasms (West syndrome).
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DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis TABLE 1 Categories of Evidence Category Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines Vaccine Safety Committee 1 No evidence bearing on causality No evidence bearing on causality 2 Evidence insufficient to indicate a causal relation The evidence is inadequate to accept or reject a causal relation 3 Evidence does not indicate a causal relation The evidence favors rejection of a causal relation 4 Evidence is consistent with a causal relation The evidence favors acceptance of a causal relation 5 Evidence indicates a causal relation The evidence establishes a causal relation Source: Institute of Medicine, 1991, 1994.
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DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis In subsequent sections of this report and as customarily done in discussions of the NCES data, the first three categories are subsumed under the heading “encephalopathies,” whereas severe or complicated convulsions are divided into the categories “febrile” and “other.” The NCES investigators deliberately cast a wide net in identifying case children. The implication of this is discussed in a subsequent section. For each case child there were two age-, sex-, and residence-matched control children. Immunization histories were collected from immunization records; other details came from interviews with parents or from hospital records. Immunization histories were available for 904 case children with diagnoses of encephalopathies or convulsions. Of those 904 children, 43 percent were in the encephalopathy group and 57 percent were in the convulsion group (approximately two thirds of the children in the convulsion group were “febrile” and one third were “other”). Thirty of these 904 case children had received DPT within 7 days of onset of the neurologic symptoms. The authors did not include cases with infantile spasms in the calculations regarding DPT on the basis of post-hoc analyses showing no association between infantile spasms and earlier DPT immunization. In comparison, 23 of 1,783 controls (matched by age, sex, and residence but who did not have an acute neurologic illness) had received DPT within 7 days of being the exact age of their matched case child at the time of onset of symptoms in the case child, yielding a relative risk (RR) estimate of 3.3 with a 95 percent confidence interval (CI) of 1.7 to 6.5. The NCES study design has been critiqued many times in the literature (IOM, 1991). The focus of much of the criticism concerns potential sources of bias and error in case ascertainment, difficulties in determining the onset of illness, lack of control for potential confounding factors, and imprecise definitions of the clinical conditions (e.g., children whose encephalitis was possibly of infectious origin were not excluded from the study). The investigators and others have suggested that many of the biases would have led to an underestimate of the RR estimates, which would not undermine the overall conclusions (Fine and Chen, 1992; Miller et al., 1993). Other controlled studies investigating the relation between DPT and acute encephalopathy (Gale et al., 1990; Griffin et al., 1990; Walker et al., 1988) did not detect a statistically significant elevated RR for acute neurologic illness after DPT, but those studies lacked sufficient statistical power to detect any but a very large risk. The number of cases of encephalopathy in these studies was consistent with the attributable risks found in the NCES (IOM, 1991). Because of this consistency and despite the criticisms of the NCES, the IOM Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines concluded, “The evidence is consistent with a causal relation between DPT and acute encephalopathy” (IOM, 1991, p. 118). The committee further concluded that the range of excess risk of acute encephalopathy following DPT immunization is consistent with that estimated in the NCES: 0.0 to 10.5 per million immunizations. (See the 1991 IOM report for a full discussion of this issue.)
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DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis The NCES results available in 1991 were less useful to that committee in assessing the possible causal relation between DPT and permanent neurologic damage. A 12-month follow-up yielded an RR of 4.7 (95 percent CI, 1.1 to 28.0; Miller et al., 1985). However, the children were too young for a well-founded assessment of their neurologic status and the analysis was incomplete—the outcome measures were not well described and control children were not assessed in the same manner as case children. In addition, the neurologic status of the children prior to the acute event might not have been studied in a rigorous manner. The results of a 10-year follow-up were also incompletely reported (Madge et al., 1990) These data have since been reported in full (Madge et al., 1993; Miller et al., 1993). The National Childhood Encephalopathy Study—1993 Madge, Miller, and colleagues published the results from the 10-year follow-up of the NCES (Madge et al., 1993; Miller et al., 1993); 983 of the original case children and 1,012 control children were traced (the investigators attempted to trace only one of the two original matched controls). By the time of follow-up, 190 of the original case children and 4 control children had died. Outcomes were assessed for 754 case children and 976 control children (in addition to those who had died). Follow-up assessments were conducted by contacting school teachers, school doctors, family doctors, and parents. In an attempt to minimize bias, neither physicians nor teachers were informed of the child's status as a case or a control or of the child's immunization history, (although it is possible that parents of case children with concerns about the effects of DPT might have told the physicians or teachers of the child's history, thus possibly biasing some aspects of the follow-up assessments). Areas of dysfunction detected on examination or reported on questionnaires were quite broad and included neurologic, motor, sensory, educational, behavioral, and self-care dysfunctions. Detailed descriptions of the measures can be found in the report by Madge et al. (1993). Neurologic dysfunction was indicated by any of (a) a definite or possible neurologic disorder as judged by a physician who examined the child, (b) information from parents or physician that the child had convulsions or took anticonvulsant medication in the previous 2 years or had a diagnosis of epilepsy, or (c) a medical diagnosis of cerebral palsy or a related disorder. Detection by a physician of noticeable tremor, gross motor incoordination, fine motor incoordination, motor impersistence, muscle weakness or spasticity in one or more limbs, or abnormal tendon reflexes in one or more limbs indicated motor dysfunction. Sensory impairment was indicated if children could not detect sounds of 25 dB at 250 Hz and 20 dB at all other frequencies, or if a test of
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DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis either near or distant vision in the best eye was abnormal. Global educational ability was measured with a combination of scores attained on intelligence, vocabulary, spelling, reading, and arithmetic tests. A score of less than the fifth percentile of control children was categorized as an indication of dysfunction. The Rutter A(2) Parent Questionnaire and the B(2) Teacher Questionnaire were used to measure behavior. Behavioral dysfunction was indicated if the child had problem behavior, hyperactive behavior, unsociable behavior, or any combination of the three behaviors and if that same behavior occurred both at home and at school. Self-care ability was based on whether the child lost control of his or her bladder or bowels at least once a week. Case children (i.e., children who had experienced a serious acute neurologic illness between ages 2 and 35 months) were more likely than controls to have died or shown some form of dysfunction. This is analyzed in great detail in the report by Madge et al. (1993). The proportion of children who had any dysfunction or died was highest for those with a diagnosis of infantile spasms as the acute event (90 percent); this was followed by nonfebrile severe convulsions (85 percent), encephalopathy (77 percent), and severe febrile convulsions (44 percent). In contrast, only 24 percent of control children had any dysfunction or had died at follow-up. The authors then investigated the relation between DPT vaccination 7 days prior to the acute illness and long-term outcome in the original study children (Miller et al., 1993). Unfortunately, that analysis excluded the case children with the initial diagnosis of infantile spasms on the basis of a post hoc analysis showing no association between infantile spasms and earlier DPT immunization. The analysis also excluded case children with recognized neurologic defects prior to the acute neurologic illness, although the neurologic status of very young children is difficult to assess and therefore such assessments might not have been done in a rigorous manner. Of the 770 case children reported to have had no apparent neurologic illness prior to the initial illness, 594 were traced and assessed. Of those 594 case children, 367 had died (n = 117) or had some dysfunction (n = 250) at follow-up; 12 of those 367 children had been immunized with DPT within 7 days prior to the acute illness (Miller et al., 1993). This rate was significantly higher than expected by comparison with matched controls (RR, 5.5; 95 percent CI, 1.6 to 23.7). Restriction of the comparison to children who had more serious dysfunctions at follow-up (i.e., children who had neurologic, educational, or behavioral dysfunction or who had died) yielded a higher RR (RR, 7.3; 95 percent CI, 1.9 to 40.9). Case children who had received DPT within 7 days prior to the acute event were no more or no less likely to have died or experienced dysfunction at the 10-year follow-up (66.7%) than case children who had not been vaccinated with DPT within 7 days prior to the acute event (61.6%).
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