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6
Evidence Concerning Pertussis Vaccines and Other Illnesses and
Conditions
ANAPHYLAXIS
Clinical Description and Pathologic
Aspects
The term anaphylaxis generally refers to a sudden,
potentially life-threatening, systemic condition mediated by highly
reactive molecules released from mast cells and basophils.
Mediators include histamine, platelet-activating factor, and
products of arachidonic acid metabolism (Fisher, 1987). Release of
mediators depends typically upon the interaction of antigen with
specific antibodies of the immunoglobulin E (IgE) class that are
bound to the mast cells and basophils. Antibodies of other
immunoglobulin classes are thought to mediate anaphylaxis on
occasion. By definition, the antibodies are formed by prior
exposure to the same or a closely related antigen. Anaphylaxis
results from widespread release of mediators that enter the
circulation, and thus, anaphylaxis is an expression of allergy that
is systemic. At a cellular level, the reaction begins within
seconds of exposure to the inciting antigen. However, depending
upon the degree of sensitization (IgE antibody formation), and
presumably upon the rate with which the antigen enters the
circulation, localized or systemic symptoms may not be expressed
for minutes or a few hours (Dolovich et al., 1973; Pearlman and
Bierman, 1989). Symptoms are due to leaking of fluid from blood
vessels, constriction of smooth muscle in certain viscera, and
relaxation of vascular
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smooth muscle. Classic symptoms include pallor and then diffuse
erythema, urticaria and itching, subcutaneous edema, edema and
spasm of the larynx, wheezing, tachycardia, hypotension, and
hypovolemic shock (Kniker, 1988; Pearlman and Bierman, 1989). If
death occurs, it is most commonly from airway obstruction caused by
laryngeal edema or bronchospasm, or cardiovascular collapse from
transudation of fluids from the intravascular space (Pearlman and
Bierman, 1989). The tissues at autopsy show primarily widespread
edema.
The clinical presentation of anaphylaxis can be produced by
intravascular antigen-antibody reactions that activate the
complement system. In this case, the antibodies may be of the IgG
or IgM class. Peptides that are split from activated complement
components act on mast cells and basophils to induce the release of
the same mediators (Kniker, 1988). This reaction is recognized most
clearly after intravenous administration of antigen; it has been
hypothesized to occur rarely after intramuscular or subcutaneous
injection through rapid entry (within 1 to 5 minutes) of large
amounts of the antigen into the venous circulation. This reaction
in an infant presumably could be mediated by IgG antibody received
transplacentally from the mother; such antibody would be expected
to persist for the first 6 months of life and possibly longer
(Benacerraf and Kabat, 1950; Cohen and Scadron, 1946). Anaphylaxis
also can occur without an obvious cause (Wiggins et al., 1989).
Shock caused by bacteremia with circulating bacterial endotoxin
also appears to involve activation of the complement system (Fearon
et al., 1975; Lachmann and Peters, 1982). Endotoxin shock has a
clinical presentation different from that of anaphylaxis, however;
it develops more slowly and is almost always associated with
disseminated intravascular coagulation, with consumption of
clotting factors and hemorrhage (Colman, 1989; Suffredini et al.,
1989a,b). Endotoxin elicits the release of mediators of
inflammation in addition to those from mast cells and basophils,
including interleukin-1 and tumor necrosis factor (Michie et al.,
1988; Morrison and Ryan, 1987). The Jarisch-Herxheimer reaction,
described classically in patients with spirochetal disease within
hours after beginning drug therapy, may be a form of endotoxemia
or, at least, complement activation caused by circulating bacterial
products (Bryceson, 1976).
The Arthus reaction is another immunologic response that can be
associated with tissue damage. This reaction is mediated
differently from anaphylaxis. The formation of antigen-antibody
complexes with deposition in the walls of blood vessels is basic to
this reaction. This is not an acute, immediately overwhelming
condition. It generally develops over 12 to 24 hours if antibody
levels are already high, or it can develop over several days (e.g.,
in serum sickness) as antibody levels increase and antigen
persists. In this reaction, immune complexes in the walls of blood
vessels
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initiate an inflammatory reaction involving complement and white
blood cells, particularly neutrophils. Tissue sections show acute
inflammation, and profound tissue destruction can occur. The most
common target organs in an Arthus-type reaction include kidney,
skin, joints, lung, and brain (Henson, 1982).
History of Suspected Association with
Pertussis Vaccines
Identical twins died 16 and 20 hours after their second DPT shot
given at age 10 months (Werne and Garrow, 1946). Autopsy showed
evidence of the vascular smooth muscle contraction and increased
capillary permeability expected with anaphylaxis. Adverse reactions
were not reported in other infants who received the same batch of
vaccine. The injected material was sterile. The delayed response
was noted to be atypical of the anaphylactic reactions reported to
that time. The authors found no cases of anaphylactic reactions to
DPT reported in the world's literature.
Evidence from Studies in Humans
Case Reports and Controlled
Epidemiologic Studies
Anaphylaxis with shock is uncommon in infancy, but the exact
frequency is unknown. Since the original reports in 1946,
''anaphylaxis" (sometimes used less strictly to apply to any type I
or immediate hypersensitivity reaction) has been reported in
additional infants after routine immunization with DPT. Osvath and
colleagues (1979) reported 31 total complications that developed
within 36 hours of injection of DPT vaccine into an estimated
300,000 children in Hungary. Five of the 31 reactions were
urticaria, which is typically an IgE-mediated response; 7 other
infants had severe shock with loss of consciousness (not
necessarily allergic in origin) or laryngeal edema, a rate of 2.3
such reactions per 100,000 injections. Eight of these 12
reactions occurred after the first injection, when specific IgE
antibodies would not be expected to be present. (These are not
passed from mother to infant across the placenta.) IgG antibodies
to antigens in DPT might be present, however. Serum total IgE
levels were considered "moderately elevated" in 29 of the total 31
infants; the 2 babies with normal IgE levels were among those with
allergic symptoms. Thus, serum IgE levels were not helpful in
considering the possibility of allergy in these patients, and
anaphylaxis was not proven.
Pollock and Morris (1983) analyzed data from the North West
Thames region of England, where an intensified effort over the
previous 7 years had
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been undertaken to identify all severe adverse events following
immunization. The authors identified events in two different ways:
one derived from physicians' voluntary reports and the other from
systematic review of hospital discharge diagnoses. Approximately
134,700 children completed courses of three doses of DPT vaccine
(404,000 doses), and 135,500 children completed courses of DT
vaccines. Eight children exhibited symptoms of anaphylaxis or
collapse within 24 hours of receipt of DPT vaccine (some within
minutes), for a rate of 6 cases per 100,000 children vaccinated (2
cases per 100,000 injections); an additional eight children
exhibited similar symptoms after receiving primary or booster DT
vaccine for an identical rate. The timing suggests that at least
some of these cases may have been anaphylaxis. All children
recovered without sequelae.
One hundred eighty-seven cases of anaphylaxis (ICD 9 code
995.0/999.4) 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). Of these 187 cases, 130 (70 percent) also received at least
one other vaccine at the time of DPT immunization. No follow-up of
the cases was made, and a physician's diagnosis was not
required.
Two recent case reports (one an adult) describe a close temporal
relationship between injection of DPT vaccine and an anaphylactic
reaction (Leung, 1985; Ovens, 1986). Both patients survived without
apparent long-term adverse effects.
Occurrence of a hypotonic, hyporesponsive state, or actual
"collapse," has been reported after DPT administration (Cody et
al., 1981; Galazka and Andrzejczak-Kardymowicz, 1972; Health
Council of The Netherlands, 1987, 1988; Hopper, 1961). Its onset
between 1 and 12 hours after immunization is compatible with an
anaphylactic reaction, but other explanations are possible. Data
regarding pathophysiology have not been given. (See the description
of hypotonic, hyporesponsive episodes later in this chapter.)
Three of 13 children given three injections of DPT produced IgE
antibody (in low levels) to the one pertussis antigen tested,
pertussis toxin (PT) (Hedenskog et al., 1989), demonstrating that
at least a weak IgE antibody response can occur after
immunization.
Bordetella pertussis vaccine has been shown to increase
the sensitivity of rodents to the effects of injected histamine
(Arora et al., 1970; Munoz, 1985; Munoz and Bergman, 1968).
Conceivably related is the finding that intradermal injection of
histamine produced significantly larger wheals in infants after
(compared to before) immunization with DPT vaccine (Sen et al.,
1974). Results were maximal after 24 hours and increased markedly
for 5 to 7 days. Reactions were equivalent after the first, second,
or third
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DPT shots. Injection of DT into children aged 2 to 5 years (a
control group) did not increase the dermal response to histamine,
but this population was not age-matched to that given DPT. It is
not clear that these findings have any relationship to the
occurrence of anaphylaxis after injection of DPT.
A 45-year-old male volunteer who was hyperimmunized with
pertussis vaccine (eight shots of 2.4 NIH [National Institutes of
Health] protective units each) to produce anti-pertussis immune
globulin died of progressive renal failure secondary to a chronic
diffuse vasculitis (Bishop et al., 1966). No etiology was proven
for the vasculitis, but the case raises the possibility that an
Arthus-type reaction was initiated by an antigen in the vaccine.
The extraordinary hyperimmunization makes it impossible to
extrapolate to possible responses to standard immunization
practices.
Evidence from Studies in Animals
Pertussis vaccine is said to act as an adjuvant in the formation
of skinsensitizing, IgE-like antibody in mice and rats (Clausen et
al., 1970; Munoz and Bergman, 1977). At least two substances in the
DPT vaccine, PT protein and endotoxin, are believed to have the
potential for such an adjuvant effect (Munoz and Bergman, 1977;
Tada et al., 1972).
Injection of B. pertussis vaccine has been shown to
facilitate the induction of anaphylactic shock in the rat and mouse
but not in the hamster, guinea pig, rabbit, or dog (Arora et al.,
1970; Chang and Gottshall, 1974; Csaba and Muszbek, 1972; Munoz et
al., 1987).
Injection of pertussis vaccine (0.1 ml/mouse, roughly 200 times
the human dose) increased the susceptibility of mice to the lethal
effects of various bacterial endotoxins injected subsequently
(Kind, 1958). The increased endotoxin sensitivity was not present 1
or 3 days after administration of pertussis vaccine but was
pronounced after 5 to 20 days.
Steinman and colleagues (1982) have developed a mouse model in
which they can regularly induce a lethal shock-like syndrome by
injection of 3 x 1010 heat-killed
B. pertussis into mice sensitized by repeated injections of
1 mg of bovine serum albumin. Only mouse strains with certain
histocompatibility (H-2) genotypes are susceptible, which is
compatible with an immunologic basis for the reaction. PT is
required for induction of this toxicity (Steinman et al., 1985),
and immunization with PT antigens protects the mice against the
reaction (Oksenberg et al., 1989). Pretreatment of the mice with
histamine H1 receptor antagonists also protected the mice; this
result is compatible with an allergic-immunologic basis for the
reaction, but it does not prove such, since other actions of the
antagonists are possible (Peroutka et al., 1987). Relatively large
doses of pertussis vaccine and sensitizing antigen are used in this
model compared with injections given to
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humans; a particular immunizing schedule and certain mouse
strains are required. Thus, the relevance of this reaction to that
in infants is speculative. Munoz and colleagues (1987) and
Wiedmeier and colleagues (1987) have described data suggesting that
this reaction represents anaphylaxis and not encephalopathy, as
some had hypothesized. The development of the reaction was
unrelated to the capacity of PT to act as a toxin through its
characteristic activity of ribosylation of key cellular proteins
(Wiedmeier et al., 1987).
Endotoxin
Commercial DPT vaccines across the world have been reported to
contain bacterial endotoxin, usually in concentrations of about l
to 10 µg/ml (Geier et al., 1978; Ibsen et al., 1988). There
was a direct correlation between endotoxin content and the
percentage of DPT vaccine recipients who developed fever (Baraff et
al., 1989), and it has been questioned whether the endotoxin in DPT
vaccine might be responsible, at least in part, for immunologic
reactions or encephalopathy. Animal studies have been cited in
support of this hypothesis, for example, those showing that
endotoxin or DPT vaccine can induce an increase in the permeability
of cerebral blood vessels, which might predispose an individual to
brain damage (Amiel, 1976; Bergman et al., 1978; Eckman et al.,
1958). However, the use of animals to explore this hypothesis is
complicated by the fact that different species respond differently
to different endotoxins. Moreover, endotoxins from different
bacteria cannot be compared on the basis of weight since weight
does not accurately reflect biologic activity (Chaby et al., 1979).
In short, data do not exist at present to indicate that the
endotoxin present in DPT vaccines plays a role in the anaphylaxis
associated with injection of DPT. Nor do data exist to support a
role for endotoxin in the other immunologic reactions or in the
encephalopathies that have been suspected sequelae of DPT
immunization.
Summary
The body of evidence concerning the possible relation between
vaccination with DPT or its pertussis component and anaphylaxis
includes a number of case reports, case series, studies in animals,
and one controlled epidemiologic study. Anaphylaxis is rare in
infants in the absence of an obvious exciting cause. Rates of
anaphylaxis estimated from two reports (Osvath et al., 1979;
Pollock and Morris, 1983) have been approximately 2 per 100,000
injections. The clinical presentation of cases with rapid onset
after injection of vaccine and (in two cases) autopsy findings
suggest that anaphylaxis can be caused by DPT injection. Laboratory
studies to link an
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immunologic reaction with the clinical event in such cases have
not been reported, however. Specifically, no exciting antigen has
been demonstrated, and whether or not specific antibody of the IgE
(or another) class is required for such events to occur after DPT
injection has not been shown. It has been postulated that endotoxin
in the DPT vaccine might be involved in tissue damage distant from
the site of injection or that an Arthus- or Jarisch-Herxheimer-type
reaction might be initiated by constituents in the DPT vaccine;
however, the clinical presentations and the pathologic findings,
when available, of the adverse events discussed in this report do
not clearly support these hypotheses. Furthermore, the animal
models described to date employ antigen loads, dosage schedules,
pathologic endpoints, add-on antigens, or other experimental
conditions that deviate from the human situation that is the
subject of concern. Consequently, although the data from animal
experiments may be useful in formulating or modifying hypotheses,
they do not implicate an immunologic or endotoxin-initiated basis
for possible adverse events following DPT immunization.
The possibility of a causal relation with anaphylaxis is
supported by biologic plausibility and clinical observation.
Biologic plausibility derives largely from the knowledge that
injection of foreign proteins into humans (and there are many
foreign proteins in DPT vaccine) can be expected to elicit in some
percentage of recipients IgE-mediated responses that present as
anaphylaxis. The biochemical, immunologic, or immunohistologic
techniques that could provide relevant evidence have not been
applied. Nevertheless, the classic presentation and timing strongly
suggest that DPT injection can cause anaphylaxis.
Reports of hives or angioneurotic edema following DPT
administration have been obtained only through the CDC's MSAEFI
system and are not well substantiated. Furthermore, in contrast to
anaphylaxis, the occurrence of hives or angioneurotic edema in
infancy without a known cause is not rare, so that the concurrence
of DPT immunization and these conditions is, therefore, more likely
to be observed coincidentally than anaphylaxis is. No biologically
meaningful connection can be said, at present, to exist between DPT
injection and hives, angioneurotic edema, an Arthus or
Jarisch-Herxheimer reaction, or endotoxin-mediated tissue
damage.
Conclusion
The evidence indicates a causal relation between DPT vaccine and
anaphylaxis, although there is no reason to implicate the pertussis
component more than the diphtheria or tetanus components of DPT
vaccine. In the absence of formal studies of incidence, rates of
anaphylaxis are estimated to be approximately 2 cases per 100,000
injections of DPT (6 per 100,000 children given three doses of
DPT).
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AUTISM
Clinical Description
Infantile autism represents one of the group of disorders now
referred to as pervasive developmental disorders (Rutter, 1985;
Volkmar and Cohen, 1986). The disorder, termed autism by
Kanner in 1943, is characterized as having its onset before age 30
months, with disturbances in social relationships and language and
stereotyped behaviors. Autistic children exhibit a failure to
develop specific attachment relationships. For example, they do not
follow their parents around the house or go to them to seek
comfort, and they frequently fail to use eye contact as a social
signal. Their language acquisition is not only markedly delayed but
they fail to use social imitation. Most importantly, they fail to
use speech for social communication. Little is known of the
etiology or pathogenesis of autism. Two-thirds of autistic children
remain severely disabled as adults, but a small percentage are able
to work and interact with other individuals.
Descriptive Epidemiology
Prevalence rates of autism are estimated to be between 4 and 5
per 100,000 children under age 15 years (Wing et al., 1976). Rates
are lower when administrative records, rather than interviews or
case reviews, are used and when more restricted definitions of the
syndrome are employed (DeMyer et al., 1981). Prevalence rates of
autism must be viewed with caution given the heterogeneity of case
definitions of pervasive developmental disorders and potential for
biased case detection (Volkmar and Cohen, 1986). All studies report
a higher incidence in males, with a male:female sex ratio on the
order of 3:1 to 4:1 (Wing, 1981); however, girls as a group may be
more severely affected (Volkmar and Cohen, 1986). An increased
incidence of prenatal and perinatal complications has been noted in
cases of pervasive developmental disorders (DeMyer et al., 1981).
However, factors such as maternal age at birth, birth order,
ordinal position, and season of birth have not been related to
incidence rates (Volkmar and Cohen, 1986).
Evidence from Studies in Humans
The committee identified no case reports or other studies of
autism following pertussis immunization. The sources examined
include the CDC's MSAEFI system, which received no reports of
autism (ICD 9 code 299.0) occurring within 28 days of DPT
immunization 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
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for Disease Control, personal communication, 1990). The lack of
reports of cases within 28 days of DPT immunization is not
surprising, however, given that a diagnosis of autism is difficult,
if not impossible, before age 3 years.
Summary
No data were identified that address the question of a relation
between vaccination with DPT or its pertussis component and autism.
There are no experimental data bearing on a possible biologic
mechanism.
Conclusion
There is no evidence to indicate a causal relation between DPT
vaccine or the pertussis component of DPT vaccine and autism.
ERYTHEMA MULTIFORME OR OTHER RASH
Clinical Description
Erythema multiforme is an acute, self-limited eruption
characterized by symmetric erythematous, edematous, or bullous
lesions of the skin or mucous membranes (or both) that pass through
multiple morphologic stages (Hebra, 1866). A hypersensitivity
reaction to a number of substances, including infectious agents, is
a proposed mechanism, but the pathophysiology has not been
defined.
Descriptive Epidemiology
Erythema multiforme, although rare, can occur in infancy and
childhood. No population-based incidence rates were identified for
the pediatric population.
Evidence from Studies in Humans
Case Reports
Erythema multiforme has been reported in association with
several vaccines, including DPT (Leung, 1984; Leung and Szabo,
1987). These reports describe three cases, ranging in age from 2
months to 19 months, in which a maculopapular rash consisting of
symmetrical lesions with central clearing ("iris" lesions)
developed following DPT vaccination. A fourth case in a 5-year-old
consisted of blisters on an erythematous base. The eruptions
occurred from 2 hours to 3 days after receiving DPT vaccine and, at
least in
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two cases, cleared spontaneously within several days. The
outcome in the other two cases was not reported.
Ten cases of erythema multiforme (ICD 9 code 695.1) 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). Of these 10 cases, 5
received oral poliovirus vaccine (OPV) at the time of DPT
immunization, 1 case received OPV plus Haemophilus
influenzae type b vaccine with DPT, and 3 cases received OPV
plus measles-mumps-rubella vaccine (MMR) with DPT. No follow-up of
the cases was made, and a physician's diagnosis was not required.
If all 10 cases represent a reaction to DPT, which is unlikely in
view of the long time frame and the administration of other
vaccines, the frequency of erythema multiforme after DPT
immunization would be approximately 1 per 8 million doses of
DPT.
Rash as an adverse reaction to DPT vaccine appears to be rare;
several reports of large series do not mention rashes (Cody et al.,
1981). Isolated case reports describe a variety of self-limited
rashes following DPT immunization, ranging from eczematous
reactions (Hopper, 1961; Illingworth, 1987) and macular rashes
involving the head and trunk (Hopper, 1961; Denning et al., 1987)
to localized lesions at the injection site (Laude, 1981; Orlans and
Verbov, 1982). None of these reports presents evidence specifically
implicating the pertussis component of the vaccine.
Pertussis vaccine has been associated with increased skin
reactions to injected histamine in mice (e.g., Parfentjev and
Goodline, 1948). Various heat-killed gram-negative bacteria as well
as their common endotoxin, lipopolysaccharide W, injected
intradermally into a patient with erythema multiforme have
reproduced its classic iris lesions (Shelley, 1980). Denning and
colleagues (1987) raised the possibility that vaccine-associated
rash may be due to the preservative thiomersal.
Aluminum Salts
The possibility has been raised that the aluminum salts
regularly present in DPT vaccines might cause
vaccination-associated rashes (see Appendix E for discussion).
There are no data to indicate that aluminum salts play a role in
DPT-associated rashes.
Summary
The body of evidence concerning the possible relation between
vaccination with DPT or its pertussis component and erythema
multiforme or other rash is limited to 4 cases reported in the
literature and 10 unconfirmed cases
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reported through the CDC's MSAEFI system. The unambiguous
clinical presentation of erythema multiforme suggests that the
vaccine exposure truly preceded the event. The relation is
biologically plausible, since erythema multiforme is thought to be
a dermal hypersensitivity reaction to a drug or other foreign
antigen and pertussis vaccine could provide such a sensitizing
antigen.
The temporal relation between DPT injection and the onset of
rash suggests a possible causal relation. However, only four cases
of such a relation have been documented, and none specifically
implicates the pertussis component of the vaccine.
Conclusion
There is insufficient evidence to indicate a causal relation
between DPT vaccine or the pertussis component of DPT vaccine and
erythema multiforme or other rash.
GUILLAIN-BARRÉ SYNDROME
(POLYNEUROPATHY)
Clinical Description
The condition referred to as the Guillain-Barrè syndrome
(GBS) was described by Chomel (1828), Graves (1843), Landry (1859),
and Guillain, Barrè, and Strohl (1916) and is variously
known as acute idiopathic, acute inflammatory, and postinfectious
polyradiculopathy or polyneuropathy. The term
Guillain-Barrè syndrome avoids the historical confusion
and etiologic uncertainty of this disorder (Lancet, 1988). The
severity and duration of the illness depends upon the degree to
which spinal roots and peripheral nerves are affected by focal
inflammation.
Infectious agents and other trigger factors have been thought to
precipitate the illness. An epidemic of acute polyneuritis formed
the basis for Chomel's original description. A more recent example
is the association seen between influenza vaccination and GBS in
1976. Human immunodeficiency virus infection and Lyme disease are
being increasingly identified as causes of acute painful
polyradiculitis. Other infectious agents have been associated with
the onset of GBS, including cytomegalovirus, Epstein-Barr virus,
mycoplasma, and Campylobacter jejuni. Tetanus vaccine
has also been related to GBS (e.g., Newton and Janati, 1987;
Pollard and Selby, 1978).
Diagnosis of GBS is sometimes difficult. The classic features of
GBS are progression over days to a few weeks, relative symmetry,
mild sensory signs or symptoms, cranial nerve involvement, onset of
recovery 2 to 4 weeks after the halt of progression of symptoms,
autonomic dysfunction,
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DT. Rates of pallor and cyanosis, i.e., "hypotonia," were
similar (40 per 100,000 doses) in both the adsorbed DPT (5 cases)
and DT (4 cases) groups. The RR for HHE following DPT compared with
that following DT vaccine is 1.0 with a 95 percent CI of 0.3 to
3.3. The power of this test, like those in the other controlled
studies of HHE, was low: 50 percent for an RR of 3.5 and 80 percent
for an RR of 5.9. Four cases occurred after plain DPT, but the
major difference in the preparation of this vaccine makes
comparisons difficult. All 13 children recovered quickly, and there
were no sequelae.
Because each of these three studies had relatively low power,
the committee combined the evidence from all three using the
methods of meta-analysis described in Appendix D. The pooled RR was
1.6 with a 95 percent CI of 0.6 to 4.2 (under both the random- and
fixed-effects models). Thus, the meta-analysis provides little
evidence of a significantly increased risk of HHE following DPT
compared with that following DT vaccine.
Blumberg and colleagues (1988), in a surveillance study
conducted in Los Angeles County in 1986, identified five children
who had HHE following DPT immunization. A physical examination and
medical history were conducted on and blood samples were collected
from each child. Results were compared with those for 16 control
children, ages 4 to 6 years, who had no reactions following DPT
immunization. Acute leukocytosis (average total white cell count,
9,400 cells/mm3) was observed in
both cases and controls on the day following DPT immunization; no
abnormalities were noted in plasma insulin or serum glucose.
Follow-up at 1 month postimmunization revealed no persistent
neurologic abnormalities in the five cases of HHE.
Long and colleagues (1990) prospectively assessed the rates of
adverse events, including HHE, following pertussis vaccination in
538 children randomized to the standard four-dose immunization
schedule or to a three-dose schedule with a saline injection
substituted for DPT at age 6 months. In all, 1,553 doses of DPT
vaccine were given. No cases of HHE were observed following DPT
vaccination. However, it is not surprising that an event as
infrequent as HHE was not detected given the study's relatively
small sample size and, therefore, the study provides little
information on the presence or absence of an association between
DPT immunization and HHE.
Summary
The body of evidence concerning the possible relation between
vaccination with DPT or its pertussis component and HHE includes
case reports, case series, and several controlled epidemiologic
studies. Incidence rates of HHE vary widely, from 3.5 to 291 per
100,000 injections. Epidemiologic evidence of sufficient quality
pertinent to this question can be summarized as follows. Two of the
three controlled studies comparing children immunized with DPT or
DT (Cody et al., 1981; Pollock et al., 1984) found no association
between HHE and DPT compared with that between HHE and
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DT vaccine, and the other study (Pollock and Morris, 1983) found
a significantly increased risk that the authors ascribed to the
voluntary reporting system (Table 6-1). Dose-response relations
cannot be evaluated from the available data. The easily visualized
presentation of HHE suggests that exposure truly preceded the onset
of the condition among the exposed cases.
The pathophysiologic basis of HHE is not understood. The
clinical presentation of this adverse event includes a spectrum of
signs, ranging from decreased responsiveness to shock, and in some
reports, HHE is not differentiated from anaphylaxis. However, no
clinical signs of allergy have been reported and no laboratory
evidence for an immunologic reaction or any other mechanism has
been presented. The clinical picture in some cases resembles a
seizure, but there is no evidence for this possibility.
Nevertheless, a clinical presentation that could be classified as
HHE has been widely observed and reported. Thus, the evidence for
causality rests here on the typical clinical presentation that
occurs within a few hours after administration of the vaccine.
The evidence concerning a possible relation between HHE and
chronic neurologic damage such as mental or motor retardation
includes case reports, case series, and controlled epidemiologic
studies. A few case reports have raised the possibility that HHE
might be associated with permanent sequelae, but the three
controlled studies that have examined this issue indicate no such
relation. However, the relatively small number of HHE cases (27)
followed up in these three studies would suggest that the
likelihood that these studies would detect a rare sequela like
chronic neurologic damage would be small. In addition, the
difficulty in confirming a clear date of onset for certain types of
chronic neurologic damage such as mental and motor retardation
limits the ability to establish temporal priority of exposure among
the few exposed cases reported.
Conclusion
The evidence is consistent with a causal relation between DPT
vaccine and HHE. The available evidence does not implicate the
pertussis component specifically.
Evidence is insufficient to indicate a causal relation between
HHE following DPT immunization and the subsequent development of
permanent neurologic damage.
THROMBOCYTOPENIA
Clinical Description
The term thrombocytopenia indicates decreased platelet
numbers in the blood. Thrombocytopenia may stem from failure of
platelet production,
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Page 178
splenic sequestration of platelets, increased platelet
destruction, increased platelet utilization, or dilution of
platelets. If thrombocytopenia is severe enough, petechiae and
subcutaneous hemorrhages (purpura) may occur. The cause of
idiopathic thrombocytopenic purpura, a common form of
thrombocytopenia, is not understood. Immunologic mechanisms may be
responsible for thrombocytopenia, as described earlier for
hemolytic anemia.
Descriptive Epidemiology
Thrombocytopenia is associated with a variety of causes and is
not uncommon in pediatric practice. No population-based incidence
or prevalence rates were identified for the pediatric
population.
Evidence from Studies in Humans
Case Reports and Case Series
Hennessen and Quast (1979) reported on 149 infants experiencing
adverse events following pertussis vaccination. All cases were
reported to vaccine manufacturers in Switzerland or Germany. Two
cases of thrombocytopenia were reported on the same day by one
physician 4 weeks after vaccination of two infants.
A 16-month-old girl was hospitalized with thrombocytopenic
purpura days after receiving a booster injection of DPT and OPV
(Champsaur et al., 1982). The authors concluded after virologic,
immunologic, and animal studies that the purpura was caused by a
concomitant coxsackievirus B 5 infection.
Thirteen cases of thrombocytopenia (ICD 9 codes 287.3 and 287.5)
following DPT vaccination 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). Both cases of
thrombocytopenia also received OPV at the time of DPT vaccination,
and of the 11 cases of thrombocytopenic purpura, 6 cases also
received OPV, 1 received MMR, and 4 received OPV plus MMR. No
follow-up of the cases was made, and a physician's diagnosis was
not required.
Summary
Information concerning the possible relation between vaccination
with DPT or its pertussis component and thrombocytopenia is limited
to 3 published cases and 13 additional cases reported through the
CDC's MSAEFI
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system. The clinical presentation of thrombocytopenia limits the
ability to establish whether exposure preceded the condition among
these exposed cases. The specificity of association is also
unestablished, given the multiple possible causes of
thrombocytopenia. An immunologic basis might be proposed, but no
experimental data exist to support an immunologic or other causal
association.
Conclusion
There is insufficient evidence to indicate a causal relation
between DPT vaccine or the pertussis component of DPT vaccine and
thrombocytopenia.
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Representative terms from entire chapter:
dpt immunization