abnormal are more likely to have febrile seizures. This is discussed extensively in the IOM report that reviewed the relation between DPT and encephalopathy (IOM, 1991). The NCES eliminated from its analyses children who had obvious neurological abnormalities prior to the onset of the acute neurologic illness, but the children had not been subjected to rigorous neurologic evaluation and therefore some children with underlying abnormalities might have been missed. The inclusion of complicated febrile seizures as one of the initial case definitions, if those case children did indeed have undetected underlying neurologic abnormalities, might bias the findings on long-term follow-up.

A previous IOM committee concluded that the evidence is consistent with a causal relation between DPT and acute encephalopathy (IOM, 1991). In light of that conclusion and the new data from the NCES showing that children who experience acute neurologic illness are at risk for developing chronic nervous system dysfunction, the current committee believes that conclusions, however limited, regarding the relation between DPT and chronic nervous system dysfunction can be drawn.

CONCLUSION

General Considerations

The committee concludes that the 10-year follow-up to the National Childhood Encephalopathy Study (Madge et al., 1993; Miller et al., 1993) is a methodologically sound but limited epidemiologic analysis of the relation between serious acute neurologic events and long-term dysfunction. The study adds to the science base regarding the nature of the outcomes experienced by children who had a serious acute neurologic illness, irrespective of its cause. The study adds in a more limited way to the understanding of the relation between DPT and chronic nervous system dysfunction.

The committee concludes that the recent findings from the NCES necessitate a review of the conclusion by the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines (IOM, 1991) that the evidence is insufficient to indicate a causal relation between DPT and permanent neurologic damage.

Causality Argument

On the basis of the original NCES and other studies, the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines determined that the evidence is consistent with a causal relation between DPT and acute encephalopathy (IOM, 1991). This adverse event occurs rarely; the NCES estimated an excess risk of between 0.0 and 10.5 per million DPT



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DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis abnormal are more likely to have febrile seizures. This is discussed extensively in the IOM report that reviewed the relation between DPT and encephalopathy (IOM, 1991). The NCES eliminated from its analyses children who had obvious neurological abnormalities prior to the onset of the acute neurologic illness, but the children had not been subjected to rigorous neurologic evaluation and therefore some children with underlying abnormalities might have been missed. The inclusion of complicated febrile seizures as one of the initial case definitions, if those case children did indeed have undetected underlying neurologic abnormalities, might bias the findings on long-term follow-up. A previous IOM committee concluded that the evidence is consistent with a causal relation between DPT and acute encephalopathy (IOM, 1991). In light of that conclusion and the new data from the NCES showing that children who experience acute neurologic illness are at risk for developing chronic nervous system dysfunction, the current committee believes that conclusions, however limited, regarding the relation between DPT and chronic nervous system dysfunction can be drawn. CONCLUSION General Considerations The committee concludes that the 10-year follow-up to the National Childhood Encephalopathy Study (Madge et al., 1993; Miller et al., 1993) is a methodologically sound but limited epidemiologic analysis of the relation between serious acute neurologic events and long-term dysfunction. The study adds to the science base regarding the nature of the outcomes experienced by children who had a serious acute neurologic illness, irrespective of its cause. The study adds in a more limited way to the understanding of the relation between DPT and chronic nervous system dysfunction. The committee concludes that the recent findings from the NCES necessitate a review of the conclusion by the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines (IOM, 1991) that the evidence is insufficient to indicate a causal relation between DPT and permanent neurologic damage. Causality Argument On the basis of the original NCES and other studies, the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines determined that the evidence is consistent with a causal relation between DPT and acute encephalopathy (IOM, 1991). This adverse event occurs rarely; the NCES estimated an excess risk of between 0.0 and 10.5 per million DPT

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DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis immunizations. The newly published data from the NCES indicate that children who experience a serious acute neurologic illness are at increased risk for death or dysfunction 10 years later. Furthermore, although these data do not identify a unique “post-DPT” syndrome of long-term dysfunction, they do suggest that children who experience serious acute neurologic illnesses (as described in the original NCES as encephalopathies or as severe or complicated convulsions) within 7 days after DPT vaccination are at no different risk of experiencing a broad range of long-term dysfunctions (neurologic, behavioral, educational, motor, sensory, and self-care dysfunctions) than are all other children who experience similar serious acute neurologic illnesses. Because the NCES is the only systematic study of long-term dysfunctions after immunization with DPT, the committee can comment only on the causal relation between DPT and those long-term dysfunctions studied by the NCES (Madge et al., 1993; Miller et al., 1993). Thus, the committee concludes that some children who receive DPT and who experience a serious acute neurologic illness within 7 days thereafter would be expected to go on to experience chronic nervous system dysfunction or die. (All subsequent discussions of the risk of chronic nervous system dysfunction following serious acute neurologic illness should be interpreted to include the risk of death as a sequela to the acute illness.) The committee concludes that this might be true, but within and only within the confines of the conditions (acute and chronic) studied by the NCES. There is no evidence to suggest whether children who receive DPT and do not experience a serious acute neurologic illness are at increased risk for long-term dysfunction. The NCES did not identify clinical findings that differentiated the post-DPT group from others who had presented earlier with an acute neurologic disorder. Moreover, the fact that the acute and chronic nervous system dysfunctions identified in the NCES are so heterogeneous is compatible with the possibility that DPT vaccination may “trigger ” acute neurologic signs and symptoms in children with underlying brain or metabolic abnormalities. It is possible that the chronic nervous system dysfunction described by the NCES is the result of an underlying abnormality rather than the acute encephalopathy. It is important to note that the NCES does not provide evidence of a direct relation between DPT and chronic nervous system dysfunction, that is, in the absence of a serious acute neurologic illness that occurs within 7 days after receiving DPT. The NCES does provide data on one special or limited case of a possible relation between DPT and chronic nervous system dysfunction, situations in which a serious acute neurologic illness follows DPT vaccine within 7 days. The committee posits three plausible scenarios whereby the acute neurologic illnesses that follow DPT might be related to chronic nervous system dysfunction. Before discussing these three scenarios and the implications for causality and risk, the committee notes that the NCES data do not permit an

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DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis inference that distinguishes among these three scenarios. Thus, any conclusions drawn are based on the assumption that any one or more of these scenarios might be the “true” explanation. The committee's conclusions take into account the fact that these data do not support any one of these scenarios over the others. DPT administration might cause a serious acute neurologic illness and subsequent chronic nervous system dysfunction in children who otherwise might not have experienced either an acute neurologic illness or chronic nervous system dysfunction in the absence of DPT. If this were the sole explanation for the relation between DPT and chronic nervous system dysfunction, the committee would conclude that the relation is causal and that DPT increases the risk of chronic nervous system dysfunction in children. DPT might trigger (and thereby be an immediate or proximate cause —but nevertheless, still a cause) an acute neurologic illness and subsequent chronic nervous system dysfunction in children with underlying brain or metabolic abnormalities. These abnormalities might make the children susceptible to reacting adversely (with an acute neurologic illness) to stimuli (e.g., fever, infection, vaccines) that in children without such abnormalities might be well-tolerated. Thus, these children might have experienced chronic nervous system dysfunction even in the absence of DPT administration secondary to some other, non-DPT-related acute event. If this “triggering” by DPT of the acute event were the sole explanation for the relation between DPT and chronic nervous system dysfunction, the committee would conclude that the relation with the acute event is causal, but that DPT might not increase the overall or lifetime risk of chronic nervous system dysfunction in children, because the children who react to DPT might eventually have experienced some other type of acute illness that also could lead to chronic nervous system dysfunction. DPT might cause an acute neurologic illness in children with underlying brain or metabolic abnormalities that would themselves eventually have led to chronic nervous system dysfunction even in the absence of an acute neurologic illness. That is, the presence of underlying brain or metabolic abnormalities might predispose the child to react to DPT with an acute neurologic illness, but it is the underlying abnormality that is the cause of the chronic nervous system dysfunction, not the acute illness. DPT vaccination in this context would be a kind of “provocative challenge” unmasking the underlying abnormality. If this were the sole explanation for the relation between DPT and chronic nervous system dysfunction, the committee would conclude that the relation is not causal and that DPT administration does not increase the overall risk for chronic nervous system dysfunction.

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DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis The NCES data do not allow a distinction to be made among the three scenarios listed above. All three scenarios are consistent with a causal relation (at least in the sense of a trigger or proximate cause) between DPT and acute encephalopathy. The NCES data suggest that those children who experience acute neurologic illness might go on to develop chronic nervous system dysfunction or to die. Whether DPT can cause chronic nervous system dysfunction in those children who had experienced an acute neurologic illness within 7 days after receiving DPT is at issue in this report. The first scenario is consistent with a “causal” relation between DPT and chronic nervous system dysfunction; the third scenario is not. Whether the second scenario is consistent with a causal relation between DPT and chronic nervous system dysfunction is difficult to assess. If the children studied had experienced no acute neurologic illness other than that which occurred within 7 days after receiving DPT and the child experiences chronic nervous dysfunction, then the evidence is consistent with a causal relation between DPT and the chronic nervous system dysfunction. If the children had experienced other acute neurologic illness in addition to that following DPT, one could not say whether the evidence is consistent with a causal relation between DPT and the chronic nervous system dysfunction. Because the NCES did not (and probably could not) rule out the possibility that only children with underlying brain or metabolic abnormalities react to stimuli such as DPT with acute neurologic illness, and no other studies establish or rule out such a possibility, the committee concludes that the evidence is insufficient to indicate whether or not DPT increases the overall risk in children of chronic nervous system dysfunction. The NCES data are consistent with the possibility that some children without underlying brain or metabolic abnormalities might experience serious acute neurologic illness within 7 days after receiving DPT and that acute illness could have chronic nervous system sequelae. The NCES data also are consistent with the possibility that some children with underlying brain or metabolic abnormalities (which foster a “triggering” by DPT of an acute neurologic illness) might go on to develop chronic nervous system dysfunction due to a DPT-triggered acute illness. Therefore, the committee concludes that the balance of evidence is consistent with a causal relation between DPT and the forms of chronic nervous system dysfunction described in the NCES in those children who experience a serious acute neurologic illness within 7 days after receiving DPT vaccine. This serious acute neurologic response to DPT is a rare event. The estimated excess risk ranged from 0 to 10.5 per million immunizations (IOM, 1991). The committee stresses that this is not the strongest statement regarding causality; the evidence does not “establish” or “prove” a causal relation. The reader is referred to previous IOM reports for a more detailed explanation of these categories (IOM, 1991, 1994).