APPENDIX A
Executive Summary from Adverse Effects of Pertussis and Rubella Vaccines

Reprinted from Institute of Medicine, Adverse Effects of Pertussis and Rubella Vaccines, National Academy Press, 1991.



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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality APPENDIX A Executive Summary from Adverse Effects of Pertussis and Rubella Vaccines Reprinted from Institute of Medicine, Adverse Effects of Pertussis and Rubella Vaccines, National Academy Press, 1991.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 1 Executive Summary Next to clean water, no single intervention has had so profound an effect on reducing mortality from childhood diseases as has the widespread introduction of vaccines. Immunization, the process in which the body's own protective mechanisms are primed to thwart the invasion or multiplication of pathogens, is effective and relatively inexpensive, simple, and easy to deliver. The use of vaccines is not entirely without risk, however. Vaccines, including the whole-cell pertussis (whooping cough) vaccine and the rubella (German measles) vaccine, the subjects of this report, typically contain small quantities of material derived from disease-causing organisms. The pertussis vaccine contains dead bacteria and is termed a killed or inactivated vaccine; the rubella vaccine contains laboratory-weakened live viruses and is termed a live, attenuated vaccine. This study responds to a request to the Institute of Medicine (IOM) to conduct a thorough review of the evidence pertaining to a set of serious adverse events and immunization with pertussis or rubella vaccine. The request to IOM originated in the 1986 National Childhood Vaccine Injury Act (Public Law 99-660), whose primary purpose was to establish a federal compensation scheme for persons potentially injured by a vaccine. Section 312 of Public Law 99-660 called for IOM review of scientific and other information on specific adverse consequences of pertussis and rubella vaccines. The 11-member interdisciplinary committee, constituted

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality by IOM to conduct this study, recognized that its charge was to focus on questions of causation and not broader topics, such as cost-benefit or risk-benefit analyses of vaccination. These topics are therefore not addressed in the report. After formation of the committee, additional adverse events were added both by the committee and at the request of the Advisory Commission on Childhood Vaccines. During the 20 months of the study, the committee reviewed altogether 17 adverse events for pertussis vaccine—infantile spasms; hypsarrhythmia; aseptic meningitis; encephalopathy (including acute encephalopathy and chronic neurologic damage); deaths classified as sudden infant death syndrome (SIDS); anaphylaxis; autism; erythema multiforme or other rashes; Guillain-Barré syndrome (polyneuropathy); peripheral mononeuropathy; hemolytic anemia; juvenile diabetes; learning disabilities and hyperactivity; protracted inconsolable crying or screaming; Reye syndrome; shock and ''unusual shock-like state'' with hypotonicity, hyporesponsiveness, and short-lived convulsions (usually febrile); and thrombocytopenia—and 3 adverse events for rubella vaccine—arthritis (acute and chronic); radiculoneuritis and other neuropathies; and thrombocytopenic purpura. Although the committee was not asked expressly to examine febrile seizures, afebrile seizures, or epilepsy in relation to diphtheria-pertussis-tetanus (DPT) vaccine, it did so because these conditions may also be serious and are considered by some to be components of encephalopathy. Conclusions regarding these conditions are given in Chapter 4. The committee's conclusions on acute encephalopathy, also presented in Chapter 4, refer only to conditions diagnosed as encephalopathy, encephalitis, or encephalomyelitis. (For additional information on the committee's charge and the events leading to the enactment of Public Law 99-660, see the Preface and Appendix B, Pertussis and Rubella Vaccines: A Brief Chronology.) The following three sections of this summary briefly review the methods used by the committee to evaluate the evidence relating the 20 adverse events to pertussis or rubella vaccine, the evidence considered and the conclusions reached for each adverse event, and the research directions recommended by the committee. METHODOLOGIC CONSIDERATIONS IN EVALUATING THE EVIDENCE The committee undertook the task of judging whether each of a set of adverse events can occur as a result of exposure to pertussis or rubella vaccine. These judgments have both quantitative and qualitative aspects; they reflect the nature of the exposures, events, and populations at issue; the specific questions to be considered; the characteristics of the evidence examined; and the approach taken to evaluate that evidence. To facilitate the

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality independent assessment of the committee's conclusions, the committee wishes to make the process of its evaluation as explicit as possible. The adverse events under consideration by the committee are, in most instances, rare in the exposed population. They also are known to occur in the absence of vaccination, are clinically ill-defined, and are generally of unknown causation in the general population. The exposures—pertussis and rubella vaccinations—are very widespread in the population, so that the absence of exposure may itself require an explanation in the interpretation of comparative studies. These and other features raise a number of difficulties both in the investigation and in the evaluation of the resulting evidence. The committee considered causal questions of three kinds in connection with adverse events that have been reported to occur after administration of pertussis or rubella vaccine. The first of these questions about exposure to pertussis or rubella vaccine is, in general, can it cause the specified adverse condition? For example, can rubella vaccine cause chronic arthritis? If the conclusion is affirmative, a second question becomes pertinent: How frequently does it cause that condition? Or, how frequently is arthritis a result of rubella vaccination? The third question, which applies to a particular instance or case of an adverse event, is did it cause that specific event? Or, did rubella vaccine cause this particular individual to develop arthritis? The committee has undertaken its evaluation from a neutral posture, presuming neither the existence nor the absence of association between these vaccines and the events under consideration. The identification and acquisition of the relevant evidence were major tasks of the committee throughout the course of its work. The preponderance of this material comprised either reports of controlled, observational epidemiologic studies (case-comparison or cohort studies) or uncontrolled case reports or case series. There was no experimental evidence, whether in humans or animals, that clearly proved or disproved a causal relation. Each study or report reviewed by the committee was first assessed individually and then, as appropriate, incorporated into the collective results that underlie the committee's conclusions. Both quantitative and qualitative approaches to integration of the evidence were utilized. Formal meta-analysis was applied when it was feasible and appropriate. All of the studies were assessed insofar as possible with respect to the roles of error, bias, confounding, and chance in producing the observed results. Several considerations bearing on the inference that an association may reflect a true causal relation were also included in the committee's evaluation of the overall body of evidence pertaining to each type of adverse event under review. These included the strength of association, temporal relation between exposure and event, consistency of results between studies, specificity of the relation between exposure and event, and biologic plausibility of such a relation.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality SUMMARY AND CONCLUSIONS Table 1-1 summarizes the categories of evidence reviewed for each adverse event and the respective contribution of each to the committee's judgments about causation. The evidence is organized under five headings: (1) human experiments; (2) animal experiments; (3) case-comparison, cohort, and other controlled studies, (4) case reports and case series; and (5) biologic plausibility. Methods for interpreting evidence in the first four categories are discussed in Chapter 3. The fifth category, biologic plausibility, includes background knowledge concerning the pathophysiology of an adverse event, attributes of a particular vaccine, or other biologic information derived from research in such areas as immunology and physiology. The evidence in these five categories, elaborated in the body of the report, forms the basis of the committee's conclusions. Where evidence was available in a particular category, the committee judged whether that evidence was generally supportive or not supportive of causation or whether it was insufficient for a determination. For example, where there were relevant controlled studies which, overall, found relative risks greater than 1, the evidence was classified as "supportive of causation." Blanks for any given category of evidence indicate that evidence of that type was lacking. It is important to note that any one category of evidence generally was not sufficient in itself to support a conclusion of causality, since other aspects of the evidence, including the details of the results and the number and quality of contributing studies, as well as the assessment of the other categories of evidence, were also considered in the evaluation. Table 1-2 summarizes the committee's conclusions about the 20 adverse events evaluated in this report. As shown in the table, the committee found it convenient to organize its conclusions about the adverse events into five categories. These categories reflect the strength and direction of the conclusions about the causal relations between DPT or rubella vaccine and the 20 adverse events evaluated in the report. The bases of these conclusions are discussed in Chapters 4 through 7 of the report. Conclusions on rubella vaccine apply to the RA 27/3 rubella strain currently in use. Evidence does not differentiate between DPT vaccine and the pertussis component of DPT vaccine, except in the case of protracted crying (see below). As shown in Table 1-2, the committee found: no evidence bearing on a causal relation between DPT vaccine and autism; insufficient evidence to indicate a causal relation between DPT vaccine and aseptic meningitis, chronic neurologic damage, erythema multiforme or other rash, Guillain-Barré syndrome, hemolytic anemia, juvenile diabetes, learning disabilities and attention deficit disorder, peripheral mononeurop-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality TABLE 1-1 Categories of Evidence Reviewed for Each Adverse Event: Is the Evidence Supportive of Causation?a Vaccine and Adverse Event (Chapter of Report) Human Experiments Animal Experiments Case-Comparison, Cohort, and Other Controlled Studies Case Reports and Case Series Biologic Plausibility Yesb ?c Nod Yes ? No Yes ? No Yes ? No Yes ? No DPT Infantile spasms (4)                 X   X         Hypsarrhythmia (4)     X               X         Aseptic meningitis (4)               X     X         Acute eneephalopathye(4)         X   X     X       X   Chronic neurologic damage (4)         X     X     X     X   Sudden infant death syndrome (5)                 X   X         Anaphylaxis (6)         X     X   X     X     Autism (6) Erythema multiforme or other rash (6)                     X   X     Guillain-Barré syndrome (polyneuropathy) (6)                     X         Peripheral mononeuropathy (6)                     X         Hemolytic anemia (6)                     X   X     Juvenile diabetes (6)         X     X     X         Learning disabilities and hyperactivity (6)                 X   X         Protracted inconsokable crying and screaming (6)             X     X     X     Reye syndrome (6)               X       X      

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Vaccine and Adverse Event (Chapter of Report) Human Experiments Animal Experiments Case-Comparison, Cohort, and Other Controlled Studies Case Reports and Case Series Biologic Plausibility   Yesb ?c Nod Yes ? No Yes ? No Yes ? No Yes ? No   Shock and "unusual shocklike state" (6)               X   X       X Thrombocytopenia (6)                     X         RA 27/3 Rubella Arthritis (7) Acute X           X     X     X     Chronic   X               X     X     Radiculoneuritis and other neuropathies (7)                     X   X     Thrombocytopenic purpura (7)                     X   X     aBanks for any given category of evidence indicate that evidence of this kind is lacking. bYes, Evidence of this kind is supporative of causation. c?, Evidence of this kind is supportive of causation. dNo, Evidence of this kind is not supportive of causation. eDefind in controlled studies reviewed as encephalopathy, encephalitis, or encephalomyelitis.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality TABLE 1-2 Summary of Conclusions by Adverse Event for DPTa and RA 27/3 MMRb Vaccines   Adverse Events Reviewed   Conclusion DPT Vaccine RA 27/3 Rubella Vaccine 1. No evidence bearing on a causal relationc Autism   2. Evidence insufficient to indicate a causal relationd Aseptic meningitis Chronic neurologic damage Erythema multiforme or other rash Guillain-Barré syndrome Hemolytic anemia Juvenile diabetes Learning disabilities and attention-deficit disorder Peripheral mononeuropathy Thrombocytopenia Radiculoneuritis and other neuropathies Thrombocytopenic purpura 3. Evidence does not Indicate a causal relatione Infantile spasms Hypsarrythmia Reye syndrome Sudden infant death syndrome   4. Evidence is consistent with a causal relationf Acute encephalopathyg Shock and "unusual shocklike state" Chronic arthritis 5. Evidence indicates a causal relationh Anaphylaxis Protracted, inconsolable crying Acute arthritis aEvidence does not differentiate between DPT vaccine and the pertussis component of DPT vaccine except in the case of protracted, inconsolable crying where the evidence implicates the pertussis component specifically. bRA 27/3 MMR, Trivalent measles-mumps-rubella vaccine containing the RA 27/3 rubella strain, cNo category of evidence was found bearing on a judgment about causation (all categories of evidence left blank in Table 1-1). dRelevant evidence in one or more categories was identified but was judged to be insufficient to indicate whether or not a causal relation exists (no category of evidence checked as supporting causation in Table 1-1; exceptions are this designation under biologic plausibility for erythema multiforme and hemolytic anemia). eThe available evidence, on balance, does not indicate a causal relation (one or more categories of evidence checked as not supporting causation in Table 1-1, with evidence supporting causation being either absent or outweighed by the other evidence). fThe available evidence, on balance, tends to support a causal relation (one or more categories of evidence checked as supporting causation in Table 1-1, with evidence checked as insufficient or not supporting causation being absent or outweighed by the other evidence). gDefined in controlled studies reviewed as encephalopathy, encephalitis, or encephalomyelitis. hThe available evidence, on balance, supports a causal relation, and the evidence is more persuasive than that for conclusion 4 above (the categories of evidence are coded similarly to thos in conclusion 4, with evidence checked as insufficient or not supporting causation in Table 1-1 being absent or less than for 4).

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality athy, or thrombocytopenia, and between the currently used rubella vaccine (RA 27/3) and radiculoneuritis and other neuropathies or thrombocytopenic purpura; that the evidence does not indicate a causal relation between DPT vaccine and infantile spasms, hypsarrythmia, Reye syndrome, or SIDS; that the evidence is consistent with a causal relation between DPT vaccine and acute encephalopathy and shock and "unusual shock-like state," and between RA 27/3 rubella vaccine and chronic arthritis; and that the evidence indicates a causal relation between DPT vaccine and anaphylaxis, between the pertussis component of DPT vaccine and protracted, inconsolable crying, and between RA 27/3 rubella vaccine and acute arthritis.1 RESEARCH NEEDS In the course of its review, the committee encountered many gaps and limitations in knowledge bearing directly and indirectly on the safety of vaccines. These include inadequate understanding of the biologic mechanisms underlying adverse events following natural infection or immunization, insufficient or inconsistent information from case reports and case series, inadequate size or length of follow-up of many population-based epidemiologic studies, and limited capacity of existing surveillance systems of vaccine injury to provide persuasive evidence of causation. The committee found few experimental studies published in relation to the number of epidemiologic studies published. Clearly, if research capacity and accomplishment in these areas are not improved, future reviews of vaccine safety will be similarly handicapped. With respect to pertussis and rubella vaccines, careful review is needed to identify what sorts of questions might be best answered by further investigations and which kinds of studies could be carried out economically. The availability and introduction of new forms of pertussis vaccine, for example, could offer valuable opportunities for comparison of vaccine safety as well as efficacy. The committee's experience points to fresh possibilities and to the need for such a review. 1   The available evidence is consistent with a causal relation, but, on balance, is more persuasive than that in the previous bullet.