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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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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 riskbenefit 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-Barrè 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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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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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-Barrè syndrome, hemolytic anemia, juvenile
diabetes, learning disabilities and attention deficit disorder,
peripheral mononeurop-
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Representative terms from entire chapter:
rubella vaccine
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TABLE 1-1 Categories of Evidence Reviewed
for Each Adverse Event: Is the Evidence Supportive of
Causation?a
Vaccine and Adverse Event
Human Experiments
Experiments Animal
Case-Comparison Cohort, and Other Controlled
Studies
Case Reports
and Case Series
Biologic Plausibility
(Chapter of Report)
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 encephalopathye(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
Guillain-Barrè syndrome (polyneuropathy)
(6)
X
Peripheral mononeuropathy (6)
X
X
Hemolytic anemia (6)
X
Juvenile diabetes (6)
X
X
X
Learning disabilities and hyperactivity (6)
X
X
Protracted inconsolable crying and screaming
(6)
X
X
X
Reye syndrome (6)
X
X
Table continued on next
page
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TABLE 1-1 Continued
Vaccine and Adverse Event
Human Experiments
Animal Experiments
Case-Comparison Cohort, and Other Controlled
Studies
Case Reports
and Case Series
Biologic Plausibility
(Chapter of Report)
Yesb
?c
Nod
Yes
?
No
Yes
?
No
Yes
?
No
Yes
?
No
Shock and "unusual shock-like state" (6)
X
X
X
Thrombocytopenia (6)
X
RA 27/3 Rubella
Arthritis (7)
Acute
X
X
X
Chronic
X
X
X
X
Radiculoneuritis and other neuropathies (7)
X
X
Thrombocytopenic purpura (7)
X
X
aBlanks for any given category of
evidence indicate that evidence of this kind is lacking.
bYes, Evidence of this kind is
supportive of causation.
c?, Evidence of this kind cannot
be classified either as supportive or as not supportive of
causation.
dNo, Evidence of this kind is
not supportive of causation.
eDefined in controlled studies
reviewed as encephalopathy, encephalitis, or encephalomyelitis.
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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 shock-like
state"
Chronic arthritis
5. Evidence indicates a
causal relationh
Anaphylaxis
Protracted, inconsolable crying
Acute arthritis
a Evidence
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.
b RA 27/3
MMR, Trivalent measles-mumps-rubella vaccine containing the RA 27/3
rubella strain.
c No
category of evidence was found bearing on a judgment about
causation (all categories of evidence left blank in Table 1-1).
d Relevant
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).
e The
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).
f The
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).
g Defined
in controlled studies reviewed as encephalopathy, encephalitis, or
encephalomyelitis.
h The
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 those in conclusion
4, with evidence checked as insufficient or not supporting
causation in Table 1-1 being absent or less than for 4).
Page 8
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.
1The available
evidence is consistent with a causal relation, but, on balance, is
more persuasive than that in the previous bullet.
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