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7
Evidence Concerning Rubella Vaccines and Arthritis,
Radiculoneuritis, and Thrombocytopenic Purpura
ARTHRITIS
Clinical Description and Pathologic
Aspects
Symptoms referable to the musculoskeletal system are among the
most common side effects of rubella and of rubella vaccine. The
general term for these symptoms, arthropathy, refers to any
abnormality of the joints. Arthropathy encompasses arthralgia
(subjective pain in a joint or joints), stiffness (with arthralgia,
commonly referred to as rheumatism), and arthritis (objective
findings of swelling, redness, heat, or limitation of motion).
Arthralgia is more common than arthritis following natural rubella,
with both being more common in adults than in children (Lee et al.,
1960). Joint symptoms related to natural rubella or rubella vaccine
usually begin within 1 week of the appearance of rash in wild-type
rubella infection or within 10 to 28 days after immunization. The
joints involved, in order of decreasing frequency, are fingers,
knees, wrists, elbows, ankles, hips, and toes. The symptoms are
frequently of sudden onset and can consist of prominent stiffness
and pain only; however, warmth, redness, and effusions occur,
especially in the knees, fingers, and wrists (Smith et al.,
1987).
The subjective nature of arthralgia makes it a difficult entity
to study. Evaluation of reports of arthritis as a possible adverse
consequence of rubella vaccine is complicated by the fact that
arthritis and arthralgia are commonly subsumed under the heading
arthropathy or "joint manifestations."
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Descriptive Epidemiology
The prevalence of self-reported arthritis and arthralgia
(rheumatism), without regard to cause, in the United States has
been estimated from a number of national surveys, including the
1960-1962 National Health Examination Survey (National Center for
Health Statistics, 1964), the 1971-1975 National Health and
Nutrition Examination Survey (National Center for Health
Statistics, 1973, 1978), and the 1987 and 1988 National Health
Interview Surveys (National Center for Health Statistics, 1988,
1989). According to the 1988 National Health Interview Survey,
approximately 13 percent of respondents surveyed reported currently
having "arthritis of any kind or rheumatism." Prevalence rates
increased with age, with approximately 0.2 percent of persons under
age 18 years and 5.3 percent between ages 18 and 44 years reporting
arthritis of any kind or arthralgia. Prevalence rates were higher
in women of all ages, with 4.3 percent under age 45 years reporting
these conditions in contrast to 2.5 percent of men in the same age
group. Rates for whites and blacks under age 45 years—both
sexes combined—are 3.7 and 2.4 percent, respectively. The
combining of arthralgia and arthritis of any kind and the
cross-sectional and self-reported nature of National Health
Interview Survey data do not permit accurate assessment of the
prevalence of chronic or recurrent arthritis in the U.S.
population.
History of an Association with Rubella
Vaccines
Acute arthralgia and arthritis following vaccination have been
noted since the earliest studies of rubella vaccines (Barnes et
al., 1972; Cooper et al., 1969; Horstmann et al., 1970; Lerman et
al., 1971; Spruance and Smith, 1971; Thompson et al., 1971). These
acute events have been associated to various degrees with all
rubella vaccine strains and occur more frequently in adult women
than in adult men or prepubertal children of either sex (Plotkin,
1988; Polk et al., 1982). Reports of chronic arthropathies
following rubella vaccination have been fewer. In 1972, Spruance
and colleagues reported recurrent joint symptoms in a group of
children receiving one strain of rubella vaccine; however, it was
not until the 1980s that more systematic investigation of the
possible association of rubella vaccines with chronic arthritis was
undertaken (e.g., Cunningham and Fraser, 1985; Tingle et al., 1983,
1985, 1986). The lack of controlled studies, coupled with continued
anecdotal reports of chronic arthritis following rubella
vaccination (ABC News "20/20" report; J. Hatem, York, Pennsylvania,
personal communication, 1990; A. J. Tingle, University of British
Columbia, personal communication, 1990), have maintained a level of
concern over this possible association.
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Evidence from Studies in Humans
Acute Arthropathy and Arthritis
Case Series and Controlled Epidemiologic Studies There is
a substantial body of evidence, both from controlled and
noncontrolled studies in humans, relating rubella vaccine to acute
arthropathy and arthritis. The earliest evidence derives from
noncontrolled retrospective and prospective studies conducted in
the late 1960s and early 1970s, the former generally designed to
test the efficacy of various rubella vaccine strains, rather than
their side effects, and the latter as part of the routine
administration of the vaccine in population-based immunization
campaigns (e.g., Austin et al., 1972; Balfour et al., 1976, 1980;
Barnes et al., 1972; Cooper et al., 1969; Dudgeon et al., 1969; Fox
et al., 1976; Freestone et al., 1971; Grand et al., 1972; Kilroy et
al., 1970; Lerman et al., 1971; Monto et al., 1970; Rowlands and
Freestone, 1971; Spruance and Smith, 1971; Swartz et al., 1971;
Wallace et al., 1972; Weibel et al., 1972, 1980). The vaccines
examined in these studies were the HPV-77 strain (no longer in
use), developed in simian tissue culture and then grown for
production in dog kidney (DK) culture or in duck embryo (DEV)
culture; the Cendehill strain (in limited use now), developed in
rabbit kidney tissue culture; and the RA 27/3 strain (most commonly
used now), developed in human diploid cells (WI38).
These and more recent studies (e.g., Peltola and Heinonen, 1986;
Polk et al., 1982; Valensin et al., 1987) provide generally
consistent findings with respect to the acute arthropathy and
arthritis observed following rubella immunization. These include
the observation that arthropathy and, less commonly, arthritis
occur rarely in children but occur in 10 to 40 percent of
susceptible (seronegative for rubella at the time of immunization)
postpubertal women. Occurrence of these reactions increases with
age, and they are less frequent in men and prepubescent children.
Rates of acute arthropathy and arthritis following rubella
immunization differ by vaccine strain, with the HPV-77 (DK) variant
producing the most joint manifestations in all age groups (Barnes
et al., 1972; Spruance and Smith, 1971; Wallace et al.,
1972). The HPV-77 (DEV) and RA 27/3 strains have also been
observed to produce joint symptoms, but the symptoms are more akin
to the reaction following natural disease, and the arthropathy is
more likely to occur in adults than in children (Polk et al., 1982;
Swartz et al., 1971; Weibel et al., 1972).
In one of the few double-masked controlled studies of joint
reactions to rubella vaccine conducted to date, Polk and
colleagues (1982) compared reactions in 112 adult, seronegative
female employees of a Boston hospital receiving either the HPV-77
(DEV) or the RA 27/3 strain in response to a rubella outbreak.
Allocation to the vaccines was haphazard, because the
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supply of the initial HPV-77 (DEV) vaccine was depleted midway
through the immunization program and the RA 27/3 vaccine was
substituted in its place. Fifty-nine of the 112 women received
HPV-77 (DEV) vaccine and 53 received the RA 27/3 vaccine. Sixty
women served as controls—that is, they received one or the
other vaccine, but were seropositive for rubella at the time of
vaccination. In the HPV-77 group, 29 percent (17 of 53) reported
onset of joint manifestations and 15 percent (9 of 53) reported
onset of arthritis within the first 6 weeks following vaccination.
In the RA 27/3 group, 26 percent (14 of 53) reported joint
manifestations and 11 percent (6 of 53) reported arthritis with
onset within 6 weeks after vaccination. Among the controls, 3
percent (2 of 60) reported joint manifestations and none reported
arthritis. Joint manifestations in the HPV-77 (DEV) group occurred
later and lasted longer than those in the RA 27/3 group, but all
cases recovered without sequelae. There were 8 days missed from
work in the HPV-77 group, in contrast to 3 days in the RA 27/3
group. Using data from this study and from 22 studies published
elsewhere, the authors estimated the frequencies of joint symptoms
following administration of the four different vaccine strains to
be as shown in Table 7-1.
The relationship of acute joint manifestations to age must be
emphasized. Rubella vaccine-associated arthropathies occur rarely
in prepubertal children. In one study of the HPV-77 (DEV) vaccine,
none of 31 vaccinees under age 13 years experienced joint
manifestations, whereas 25 percent (4 of 16) of women in their 20s
and 50 percent (9 of 18) of those aged 25 to 33 had such symptoms
(Swartz et al., 1971). A later study of the same vaccine strain in
a larger number of subjects (Weibel et al., 1972) revealed similar
results. None of 276 cases of acute joint manifestations occurred
in persons under age 12 years, whereas 4 percent (6 of 157) of
persons between ages
TABLE 7-1 Frequencies of Joint Symptoms in
Adult Females Following Administration of Four Vaccine
Strains
Proportions (%) of Adult Females Developing Acute
Arthritis or Arthralgia
Vaccine
Pooled Proportion
95% Confidence Interval
No. of Studies Cited
HPV-77 (DK)
49
35-63
2
HPV-77 (DEV)
30
27-33
13
Cendehill
9
8-10
15
RA 27/3
14
13-15
9
SOURCE: Adapted from Polk et al. (1982).
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12 and 16, 9 percent (12 of 130) of persons between ages 16 and
20, 9 percent (6 of 65) of persons between ages 20 and 25, and 56
percent (14 of 25) of persons older than 25 years did. This study,
unlike the previous one by Swartz and colleagues (1971),
distinguished between acute arthritis and arthralgia and indicated
that the former was rarer, did not occur before age 16 years, and
was manifest in only 4 percent (7 of 178) of persons ages 16
through 25 years. Above age 25 years, however, acute arthritis was
common, occurring in 46 percent (11 of 24) of women immunized.
In summary, these studies provide consistent evidence that acute
arthropathy and, more rarely, acute arthritis can occur following
rubella vaccination and that incidence rates are higher in women
than in men and increase with age. None of these studies showed an
association of rubella vaccines with chronic arthropathies or
arthritis, but their generally limited sample sizes and lengths of
study follow-up make it unlikely that if there were such an
association it could have been detected. Only a few such studies
have been conducted to date, and these are described below.
Chronic Arthritis
Case Reports and Case Series A case of acute arthritis
following natural rubella that progressed to chronic arthritis was
reported in 1968 by Martenis and colleagues, and it has been
suggested that wild-type rubella virus might play a role in
juvenile rheumatoid arthritis (Hart and Marmion, 1977; Martenis et
al., 1968; Ogra et al., 1975). These suggestions have raised
concern that a possible similar progression of acute to chronic
arthritis following rubella immunization might also occur.
Lerman and colleagues (1971) reported a case of persistent
arthritis 1 year after vaccination with HPV-77 (DE) strain, and
Spruance and colleagues (1972) reported on 11 children suffering
recurrent episodes of knee stiffness, sometimes referred to as
"catcher's crouch" syndrome, 8 months after receiving HPV-77 (DK)
vaccine. This syndrome has been considered to be caused by
radiculoneuritis, rather than arthritis, as described later in this
chapter. However, follow-up of the children 11, 48, and 66 months
after vaccination indicated that 8, 4, and 3 (with 2 lost to
follow-up), respectively, of the original 11 children continued to
exhibit episodic morning stiffness in the knees (Spruance et al.,
1977). One of the cases was evaluated by arthroscopy, and the
synovium was found to be hypertrophied posteriorly; culture for
rubella virus was negative. Eleven children with recurrent
arthritis 36 months after vaccination with HPV-77 (DK) were
reported by Thompson and colleagues in 1973, and other cases have
been reported since then, some after immunization with the RA 27/3
strain (Tingle et al., 1979a,b, 1984, 1985, 1986; A. Tingle,
British Columbia Children's Hospital, personal communication,
1990). Arthritis occurring first within 12 to
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21 days after rubella vaccination has been reported to persist
for 4 to 7 years after receipt of the HPV-77 (DE) strain, for 2
years in one woman after receipt of the RA 27/3 strain (Tingle et
al., 1985), and for 3.5 years in a second woman (Tingle et al.,
1984). Two additional young adult women had recurrent arthritis or
arthralgia (not otherwise defined) for 18 to 24 months after
receipt of the RA 27/3 strain (Tingle et al., 1986).
As part of studies that began about a decade ago into the
pathogenesis of the acute arthropathy following rubella
immunization and the natural disease, Tingle and colleagues (1983)
attempted to correlate arthropathy with specific antibodies to
rubella. Seven women with recurrent arthritis were studied
retrospectively, and 24 hospital personnel were studied
prospectively. The standard assay for assessment of antibodies in
the IgG and IgM fractions, hemagglutination inhibition (HAI), and a
more sensitive enzymelinked immunosorbent assay (ELISA) were used
to study antibody at 6 weeks and 6 months after immunization. There
were no differences between those recipients who experienced joint
manifestations and those who did not. Later, in 10 of 37 adult
women volunteers who were seronegative by HAI testing and who
developed acute arthritis after RA 27/3 vaccination, Tingle and
colleagues (1983) detected prevaccination antibodies by the ELISA.
On the assumption that the standard test (HAI) failed to detect
antibodies in some preimmune individuals who tested positive by the
more sensitive ELISA, the authors suggested that the acute
arthropathy could be the result of a reinfection rather than a
primary infection. Pursuing this hypothesis, Tingle and colleagues
studied six women with recurrent chronic arthropathy, manifested by
polyarticular arthritis beginning 12 days to 3 weeks after the
immunization. Chronic arthritis was noted 2 years after vaccination
in one woman receiving the RA 27/3 strain and 4 to 7 years after
vaccination in three women receiving the HPV-77 (DE) strain.
Another woman reported chronic arthralgia more than 6 years
following receipt of the HPV-77 (DE) strain. Prevaccination sera of
three women in this group were positive by ELISA; the sera of the
other women were negative (Tingle et al., 1985).
In a later prospective study, Tingle and colleagues (1986)
compared incidence rates in two groups: the first consisted of 23
women and 23 men, ages 11 to 54 years (mean age, 19.2 years), who
had natural infection with wildtype rubella virus in 1983, all of
whom underwent seroconversion. Arthritis (joint effusion,
limitation of movement, heat, or erythema) and arthralgia, both
acute and chronic, occurred more frequently following infection
with wild-type rubella virus than it did following vaccination. In
the women who had the natural infection, 52 percent (12 of 23) had
acute arthritis and 13 percent (3 of 23) had arthralgia only. Among
the men, 65 percent (15 of 23) had some joint manifestations, 9
percent (2 of 23) had arthritis, and 48 percent (11 of 23) had
arthralgia only. These signs and symptoms became manifest within 7
to 10 days after the onset of the rash. Eighteen months
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Representative terms from entire chapter:
rubella virus
Page 193
later, 30 percent (7 of 23) of the women had joint
manifestations; of these 7 women, 4 had arthritis and 3 had
arthralgia. Among the men, 8 percent (2 of 23) had joint
manifestations; of these 2 men, 1 each had arthritis or arthralgia.
The second group consisted of 44 women students, ages 17 to 33
years (mean age, 23.1 years), given the RA 27/3 vaccine. They were
examined at weekly intervals. Within 4 weeks after vaccination, 14
percent (6 of 44) had acute arthritis and 41 percent (18 of 38) had
arthralgia only, for a total of 55 percent (24 of 44) of joint
manifestations. Eighteen months later, 5 percent (2 of 44) had
joint manifestations; it was not specified whether it was arthritis
or arthralgia.
In a study of the 1985 epidemic of rubella, Tingle (A. J.
Tingle, University of British Columbia, personal communication,
1991) examined 191 seroconverters, of whom 103 were men and 88 were
women. Forty-four percent of the women (39 of 88) and 7 percent (7
of 103) of the men had acute arthritis. Twenty-four months later,
30 percent of the women still had joint manifestations; it was not
specified whether it was arthritis or arthralgia.
In a retrospective analysis of vaccine reactions to the
measles-mumps-rubella (MMR) vaccine administered to 700,000
children in Sweden, Taranger and Wiholm (1984) reported only one
case of chronic arthritis. The patient was a 12-year-old boy who
developed "juvenile rheumatoid arthritis" 2 years after receiving
the vaccine. His HLA haplotype was B27, which has been associated
with chronic arthritis. The authors concluded that this case of
arthritis was not causally related to the vaccine, but rather was
coincidental.
Two hundred eighteen cases of arthritis (ICD 9 code 716.9)
occurring within 28 days of immunization with rubella monovalent,
measles-rubella (MR), or MMR vaccine were reported through the
CDC's MSAEFI system from 1978 to 1990, a period in which
approximately 28.8 million doses of rubella vaccines were
administered through public mechanisms in the United States (J.
Mullen, Centers for Disease Control, personal communication, 1990).
Confirmation of these cases in the form of a physician's diagnosis
was not required. Of these 218 cases, 43 (20 percent) cases
received at least one other vaccine at the time of rubella
immunization. One year after immunization, 13 (6 percent) of the
original 218 cases were reported as "not recovered"1; an additional 15 cases were lost to
follow-up at year 1.
1 Caution is
needed in interpreting this category, because cases of arthritis
with a comorbidityfor example, otitis media—reported at the
time of initial immunization and persisting at 1 year would have
been labeled "not recovered," even if the arthritis had resolved.
Review of an earlier set of acute arthritis cases subsequently
labeled "not recovered" at 1 year indicated that the majority were
due to a persisting morbidity other than arthritis (J. Mullen,
Centers for Disease Control, personal communication, 1991).
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Controlled Epidemiologic Study Polk and colleagues
(1982), in the doublemasked, controlled comparison of joint
reactions in 112 seronegative women receiving HPV-77 (DEV) or RA
27/3 vaccine described above, reported no cases of chronic or
recurrent arthritis or arthralgia. However, the average length of
study follow-up was only 6 weeks, and thus, recurrent cases might
not have been detected.
Evidence from Studies in Animals
Data from experimental studies in animals are not available,
since it has not been possible to develop an animal model for
rubella infection.
Possible Mechanisms
A suggestion that joint involvement is somehow related to stage
of the menstrual cycle has been made, but there is no evidence in
support of this hypothesis (Best et al., 1974; Lerman et al., 1971;
Swartz et al., 1971).
Pathogenesis of the joint involvement is apparently direct
infection of the synovial membrane, inasmuch as the virus has been
recovered from the joint fluid of patients with repeated episodes
of arthritis for up to 3 to 4 months after vaccination with the
HPV-77 strain (Ogra and Herd, 1971). This has also been true in
cases of rubella caused by the wild-type strain of the virus (Ogra
et al., 1975). Chantler, Tingle, and colleagues have isolated
rubella virus from peripheral blood mononuclear leukocytes of
several patients with persistent post-rubella vaccine arthritis
(Chantler et al., 1981, 1982; Tingle et al., 1985). Two of these
patients had received the RA 27/3 strain. In one study, rubella
virus was grown from the leukocytes of five of six women with
arthritis for up to 5 years after receiving the HPV-77 (DEV)
vaccine (Chantler et al., 1982). In a separate study, rubella virus
was isolated from mononuclear leukocytes from blood, synovial
fluid, or both in 7 of 19 children with chronic arthritis of
unknown cause (Chantler et al., 1985). There was no history
of recent rubella infection or rubella vaccination, although most
of the patients had received HPV-77 (DEV) rubella vaccine in the
past. The infecting rubella strain (vaccine versus wild type) was
not identified and has not been identified in the other subjects
reported to have arthropathy after rubella vaccination.
The role of circulating immune complexes (CICs) in the
pathogenesis of rubella arthritis has been suggested in one study,
in which 11 of 33 (33 percent) children with postvaccinal arthritis
had CICs containing rubella antigen, in contrast to only 3 of the
19 (16 percent) who did not experience arthralgia (Coyle et al.,
1982). In a study of adults—44 women vaccinated with the RA
27/3 strain and 23 men and 23 women convalescing from wild-
Page 195
type rubella infection—no statistically significant
differences were found in the CICs between those who had joint
manifestations and those who did not. The authors concluded that
their data ''do not support a direct role for raised CIC levels in
the pathogenesis of rubella-associated arthritis or arthralgia"
(Singh et al., 1986, p. 115).
Blood lymphocytes from 15 children who had acute
arthralgia or arthritis after rubella vaccination exhibited
depressed transformation responses to rubella virus compared with
the responses of lymphocytes from controls who had no complications
following vaccination. This finding suggests that arthritis could
result from a selective depression in the subject's cell-mediated
immunity at the time of the initial encounter with the virus (Chiba
et al., 1976). On the other hand, the lymphocyte responses to
rubella antigen in six adult women who had had recurrent
arthritis for at least 9 months after HPV-77 (DEV) rubella
vaccination were relatively elevated (Ford and Tingle, 1980; Tingle
et al., 1983). The antigens used in the two populations may have
differed. However, the two reports are not necessarily at variance,
because normal or accentuated cell-mediated immunity to the virus
would be expected over the course of an intermittent, recurrent
infection in an otherwise normal individual. In any event, it is
not clear at this time whether patients who develop arthritis,
acute or persistent, after rubella vaccination have a specific
immune system defect that prevents their systems from clearing the
virus normally.
Summary
Acute Arthropathy and Arthritis
The body of evidence concerning the possible relation between
rubella vaccine and acute joint manifestations includes a number of
case series and experimental studies comparing different rubella
vaccine strains. These studies indicate a consistent, direct
relation of all rubella vaccine strains both to acute arthropathy
and to acute arthritis, with the discontinued HPV77 vaccines being
associated with the highest reaction rates. Incidence rates
following administration of the current RA 27/3 vaccine strain to
adult women average 13 to 15 percent. Average rates are much lower
in children, increase with age, and are higher in women than in
men. Both acute arthropathy and acute arthritis are conditions
whose diagnoses are reasonably reliable; thus, the vaccine exposure
probably truly preceded onset of these adverse events in most
cases. Although acute joint manisfestations can result from a
number of different causes, their association with natural rubella
infection and the recovery of rubella virus from the joint fluid of
persons experiencing acute arthropathy or arthritis support the
biologic plausibility of a relation with attenuated rubella virus
vaccine.
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Chronic Arthritis
The body of evidence concerning the possible relation between
vaccination with MMR vaccine or its rubella component and chronic
arthritis is limited. There are several case reports and case
series, one comparative case series, and one double-masked
controlled study. Most of the patients described in these
publications had received the HPV-77 (DEV) strain of vaccine. Three
or four cases of chronic arthritis following immunization with the
RA 27/3 strain have been reported in the literature. A large number
of unconfirmed cases of chronic arthritis following administration
of RA 27/3 strain have been reported to a single institution. All
of the cases were adult females.
In the comparative case series, Tingle and colleagues (1986)
reported incidence rates of joint manifestations in 67 young adult
women following either natural infection with wild-type rubella
virus or receipt of the RA 27/ 3 strain. They reported recurrent
arthropathy more than 18 months after either natural infection or
vaccination, with incidence rates of 30 and 5 percent (two
patients), respectively. The latter two patients had "arthritis or
arthralgia" that were not otherwise described (Tingle et al., 1986,
p. 113). In a double-masked study of 112 women receiving one of two
rubella vaccine strains, Polk and colleagues (1982) reported no
cases of chronic or recurrent arthritis or arthralgia. However, the
length of the follow-up was only 6 weeks, and cases that might have
recurred later would not have been detected. In both studies, the
nature of the comparison groups precludes estimation of relative
risks for exposed versus nonexposed groups.
One of the women with chronic arthritis after vaccination with
the RA 27/3 strain had rubella virus isolated from blood
mononuclear cells and from breast milk 7 to 9 months
postvaccination. A second woman who reported recurrent arthralgia 2
years and 9 months after receipt of the RA 27/3 vaccine also had
rubella virus isolated from peripheral blood leukocytes (Tingle et
al., 1985).
The current lack of understanding of the natural history and
multiple causes of arthritis and the lack of distinction between
cases of arthralgia and arthritis in some reports diminish the
specificity of the putative association. It is also difficult to
establish whether the vaccination truly preceded the adverse event
in many cases. The association of chronic arthritis with natural
rubella infection and the recovery of a rubella virus from
leukocytes from peripheral blood and synovial fluid of women with
prolonged arthritis following rubella vaccination suggest, however,
a biologically plausible relation between rubella vaccine and
chronic arthritis. Moreover, a few cases have been documented in
which arthritis, which was ultimately judged to be chronic, began 2
to 3 weeks after vaccination, which is the incubation period of
natural rubella and the time period in which the vaccine strain can
be isolated (beginning about 1 week after injection).
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Conclusions
The evidence indicates a causal relation between the currently
used rubella vaccine strain (RA 27/3) and acute arthritis.
Incidence rates are estimated to average 13 to 15 percent among
adult women following RA 27/3 immunization with much lower levels
noted among children, adolescents, and adult men.
The evidence is consistent with a causal relation between the
currently used rubella vaccine strain (RA 27/3) and chronic
arthritis in adult women, although the evidence is limited in scope
and confined to reports from one institution.2 Prospective, double-masked, controlled
trials in which subjects are followed for at least 12 months after
rubella vaccination are needed to establish this biologically
plausible relation. Additional elements of a definitive study would
include attempts to isolate rubella virus from the synovial fluid
of affected joints of cases of arthropathy and arthritis and
molecular-genetic analysis to determine whether the isolated strain
is the one that was injected, a strain derived from the injected
strain, or an unrelated strain.
RADICULONEURITIS AND OTHER
NEUROPATHIES
Clinical Description
Radiculoneuritis is a convenient term used to describe a
combination of peripheral neuropathy with dorsal root (spinal
nerve) pain. The "catcher's crouch" syndrome, which is knee pain
that is somewhat relieved by crouching, has been suggested as an
example. This and other related conditions, including
polyneuropathy, paresthesias, and carpal tunnel syndrome, occur
sporadically in association with natural rubella infection (Bailey,
1962; Brodribb, 1963; Courtenay, 1962; Haire and Hadden, 1970;
Heathfield, 1962; Hodges, 1940; Moylan-Jones and Penny, 1962;
Witney, 1940).
Descriptive Epidemiology
Radiculoneuritis is uncommon, but it can occur at any age.
Incidence rates of related neurologic conditions have been
published for defined populations (Beghi et al., 1982, 1985;
Stevens et al., 1988).
2 When all
rubella vaccine strains, including the discontinued HPV-77 (DK) and
HPV-77 (DEV) strains, are considered as a group, the evidence
indicates a causal relation with chronic arthritis in adult
women.
Page 198
Evidence from Studies in Humans
Case Reports and Case Series
There have been reports of cases of paresthesias (Chin et al.,
1971; MortonKute, 1985; Tingle et al., 1985) and pain involving the
arms and the knees, the latter giving rise to the "catcher's
crouch" syndrome (Deinard et al., 1973; Spruance et al., 1972;
Thompson et al., 1971) following rubella vaccination. Three of
these occurred after receipt of the RA 27/3 strain (MortonKute,
1985; Tingle et al., 1985). Other related conditions, reported in
individual cases, are carpal tunnel syndrome following both HPV-77
(DK) strain (Chin et al., 1971; Thompson et al., 1971) and RA 27/3
strain (Tingle et al., 1985), two cases of optic neuritis following
administration of the HPV-77 vaccine in one case (Kazarian and
Gager, 1978) and an unstated rubella vaccine in the other (Kline et
al., 1982), three cases of transverse myelitis after Cendehill
vaccine, a vaccine of unknown rubella strain, and one unstated
vaccine (Behan, 1977; Holt et al., 1976), and two cases of
Guillain-Barrè syndrome after MMR vaccine that included the
HPV-77 (DEV) strain (Gunderman, 1973).
A case of peripheral neuropathy following rubella immunization
was reported in 1984 by Taranger and Wiholm (1984). The issue of
peripheral neuropathies related to rubella vaccines was reviewed in
an article by Schaffner and colleagues (1974), who examined reports
of 299 cases. The study concentrated on 32 children with
neuropathies who were followed for up to 32 months. Twenty of these
children recovered fully and had no recurrences; 10 had minor
complaints that persisted during the follow-up period, and 2
developed recurrences of the "catcher's crouch" syndrome after 32
and 33 weeks, respectively. The majority of the 299 total cases and
the 32 cases reviewed in detail followed administration of the
HPV-77 (DK) vaccine. The authors estimated the rate of these
complications to be 2.2 per 1,000 doses and 0.1 per 1,000 doses for
the HPV-77 (DK) and the HPV-77 (DEV) strains, respectively.
One case of radiculitis (ICD 9 code 723.4) occurring within 28
days of immunization with MR vaccine was reported through the CDC's
MSAEFI system from 1978 to 1990, a period in which approximately
28.8 million doses of rubella-containing vaccine were administered
through public mechanisms in the United States (J. Mullen, Centers
for Disease Control, personal communication, 1990). No follow-up of
the case was made, and a physician's diagnosis was not
required.
Summary
The body of evidence concerning the possible relation between
immunization with monovalent rubella or MMR vaccine and
radiculoneuritis and
Page 199
other neuropathies is limited to case reports and case series.
Frequencies of peripheral neuropathies have been estimated from
case series to be 2.2 and 0.1 per 1,000 doses of HPV-77 (DK) and
HPV-77 (DEV) vaccines, respectively. The lack of comparison groups
in these studies precludes estimation of the relative risks of
neuropathies in relation to these strains. For the RA 27/3 strain
currently in use in the United States, rates of radiculoneuritis
and other neuropathies following its receipt are not available.
Three cases have been reported after administration of this vaccine
strain. Evidence for biologic plausibility consists of the
observation that radiculoneuritis and other neuropathies can occur,
though uncommonly, after natural infection with wild-type rubella
virus.
Conclusion
There is insufficient evidence to indicate a causal relation
between the currently used rubella vaccine (RA 27/3) and
radiculoneuritis and other neuropathies.
THROMBOCYTOPENIC PURPURA
Clinical Description
Thrombocytopenic purpura presents as petechiae, purpura, or
mucosal bleeding secondary to decreased numbers of platelets in the
blood. It has been reported in association with congenital and
acquired rubella (Heggie and Robbins, 1969; Morse et al., 1966).
The estimated incidence is 1 case of thrombocytopenia in 3,000
cases of natural rubella (Bayer et al., 1965). This complication is
not unique to natural rubella, because it is estimated that 70
percent of cases of thrombocytopenia follow various viral illnesses
(Cohn, 1976). Possible mechanisms for virus-induced
thrombocytopenic purpura include generation of antibodies to a
viral antigen that cross-react with some similar antigen on the
platelet, resulting in platelet destruction (Baldini, 1966). The
virus itself or immune complexes that include the virus might
damage or otherwise modify the platelet surface, making it
susceptible to removal by the spleen. The contribution of
antibody-mediated platelet dysfunction to bleeding in patients with
idiopathic thrombocytopenic purpura, however, remains to be
established (George and Shattil, 1991).
Descriptive Epidemiology
Thrombocytopenic purpura can occur at any age. No
population-based incidence or prevalence rates were identified.
Page 200
Evidence from Studies in Humans
Case Reports
Evidence for thrombocytopenic purpura following rubella
immunization is rarer than that for natural infection and is
limited to isolated case reports. Bartos (1972) described a case of
thrombocytopenic purpura in a 26-year-old female immunized with a
monovalent vaccine. Four other cases of thrombocytopenic purpura
have been reported in a 1-year-old girl (Sharma, 1973), a
16-month-old boy and a 16-month-old girl, both of whom received the
RA 27/3 strain (Azeemuddin, 1987), and an 18-month-old girl
(Neiderud, 1983) following administration of the combined MMR
vaccine. All five patients, who were asymptomatic for viral illness
prior to immunization, developed petechiae, purpura, or mucosal
bleeding 10 days to 3 weeks postimmunization. Platelets were
markedly reduced, but peripheral red and white blood cell counts
and morphology were normal. In the patients tested, megakaryocytes
were usually increased, with an otherwise normal bone marrow. In
all cases, the postimmunization thrombocytopenia was transient. No
virus-containing immune complexes or anti-platelet antibodies were
demonstrated in these cases.
Twenty-six cases of thrombocytopenic purpura occurring within 28
days of immunization with rubella-containing vaccines were reported
through the CDC's MSAEFI system from 1978 to 1990, a period in
which approximately 28.8 million doses of rubella vaccine were
administered through public mechanisms in the United States (J.
Mullen, Centers for Disease Control, personal communication, 1990).
They were reported as idiopathic (ICD 9 code 287.3). All but 1 of
the 26 cases received at least one other antigen at the time of
rubella immunization. No follow-up of the cases was made, and a
physician's diagnosis was not required.
The report "Compensation for Vaccine-Related Injuries" (Office
of Technology Assessment, 1980) lists thrombocytopenia as a
"possible" adverse event after immunization, but cites no reference
or evidence for this conclusion. The Meruvax II (Rubella Virus
Vaccine Live, Merck Sharp & Dohme) package insert states, ''In
view of the decreases in platelet counts that have been reported,
thrombocytopenic purpura is a theoretical hazard," but it also
cites no evidence for this statement (Merck Sharp & Dohme, West
Point, Pennsylvania).
Summary
The body of evidence concerning the possible relation between
vaccination with the RA 27/3 rubella vaccine strain and
thrombocytopenic purpura is limited to two or three cases reported
in the literature and unconfirmed
Page 201
cases reported through the CDC's MSAEFI system. The unambiguous
clinical presentation of thrombocytopenic purpura would suggest
that the vaccine exposure truly preceded the event. The relation is
biologically plausible because thrombocytopenic purpura is believed
to occur rarely as a complication of natural rubella infection.
Conclusion
There is insufficient evidence to indicate a causal relation
between the currently used rubella vaccine (RA 27/3) and
thrombocytopenic purpura.
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