2adults
in developed nations are the most common source of pertussis
infections in neonates and children (Nelson, 1978).
The first recorded description of a pertussis epidemic was made
by a Parisian, Guillaume de Baillou, in 1578 (Holmes, 1940). His
characterization of the disease is graphic.
1 The terms
pertussis and whooping cough are used interchangeably
throughout this report.
2 The terms
immunization and vaccination are used interchangeably
throughout this report.
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The lung is so irritated by every attempt to
expel that which is causing the trouble it neither admits the air
nor again easily expels it. The patient is seen to swell up and as
if strangled holds his breath tightly in the middle of his throat .
. . For they are without the troublesome coughing for the space of
four or five hours at a time, then this paroxysm of coughing
returns, now so severe that blood is expelled with force through
the nose and through the mouth. Most frequently an upset stomach
follows. . . . For we have seen so many coughing in such a manner,
in whom after a vain attempt semiputrid matter in an incredible
quantity was ejected.
Opinions differ as to why a clinically characteristic disease
like pertussis was not described prior to de Baillou's description.
Kloos and colleagues (1981) suggest that the absence of a clinical
description of pertussis prior to the sixteenth century may reflect
adaptation of a close genetic variant of B. pertussis to
humans as recently as five centuries ago. Holmes (1940), in
contrast, as noted by Mortimer (1988), attributed the lack of a
prior description to an earlier preoccupation of physicians with
other serious infections such as plague, smallpox, and typhus and
to the possibility that they may have relegated the care of
pertussis patients to ''old women."
The incubation period of unmodified pertussis averages 7 to 14
days, with a maximum of 21 days (Berkow, 1987). Clinically,
pertussis can be divided into three sequential stages: the
catarrhal, paroxysmal, and convalescent stages (Cherry et al.,
1988; Mortimer, 1988). The onset of illness in the early catarrhal
stage is subtle and is generally indistinguishable from that of a
minor upper-respiratory infection. Early symptoms include
rhinorrhea, mild conjunctival injection, sneezing, anorexia,
listlessness, and a hacking nocturnal cough that gradually becomes
diurnal as well. Fever is usually absent. During this time,
coughing continues to increase in frequency and intensity and, by 7
to 10 days after the onset of illness, becomes explosive and
episodic, heralding the onset of the paroxysmal stage. The disease
is most infectious during the catarrhal stage, after which
infectivity gradually declines.
The paroxysmal stage, which lasts 1 to 4 weeks, is dominated by
severe episodes of coughing, which can occur 10 times or more in a
24-hour period. Each paroxysm is characterized by five or more
rapid short coughs followed by a deep hurried inspiration. It is
this hurried inspiration through a narrowed airway that produces
the characteristic whoop.
Paroxysms are thought to be caused by efforts to expel the thick
mucus that characteristically accumulates in the tracheobronchial
tree. During such episodes, copious amounts of this mucus are
expelled, often causing vomiting and, in infants, choking spells
and cyanosis. The child is often exhausted following a paroxysm,
although he or she can appear happy and relatively normal between
episodes. Multiple paroxysms tend to occur within
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a short period of time. A variety of stimuli, including feeding,
sucking, or crying, can trigger an attack. Very young infants tend
to have apneic spells rather than paroxysms of cough.
The convalescent stage, which usually begins 4 to 6 weeks after
the onset of disease, is characterized by a gradually diminishing
frequency and severity of paroxysms. The whoop soon disappears,
although a nonparoxysmal cough may persist for several months.
Diagnosis
B. pertussis can be cultured by inoculation of
nasopharyngeal mucus, obtained by swab, on special agar such as
Bordet-Gengou with added methicillin or Regan-Lowe with added
cephalexin. A positive culture is diagnostic. False-negative
cultures are common, particularly in persons receiving antibiotics
(Berkow, 1987). B. pertussis can also be detected by direct
immunofluorescence, although the test has been hampered by
relatively frequent false-positive and false-negative results
(Wirsing von König et al., 1990). Serologic tests, including
enzyme-linked immunosorbent assays, to detect antibody to
filamentous hemagglutinin (FHA) and other B. pertussis
components are being developed for diagnostic purposes (Berkow,
1987; Storsaeter et al., 1990; Wirsing von König et al.,
1990). Probing for Bordetella DNA, either directly or after
preliminary amplification by the polymerase chain reaction or
culture, may provide another useful means of detection (Wirsing von
König et al., 1990).
Complications
Minor complications of pertussis include subconjunctival
hemorrhages and epistaxis secondary to the paroxysmal coughing.
Suppurative otitis media is a frequent complication, especially in
infants (Mortimer, 1988).
Major complications of pertussis can be fatal. They are divided
into three general categories: respiratory, central nervous system
(CNS), and nutritional. The most common are respiratory, including
asphyxia in infants. Other severe respiratory complications include
bronchopneumonia, a frequent complication in elderly people,
atelectasis, bronchiectasis, interstitial and subcutaneous
emphysema, and pneumothorax.
CNS complications following pertussis include acute encephalitis
that can progress to convulsions, stupor, and coma. Pathologic
findings reveal cerebral hemorrhage and edema (Dolgopol, 1941).
Long-term sequelae include spastic paralysis, mental retardation,
or other permanent neurologic disorders. Rates of CNS complications
differ widely among studies. For example, 1.7 to 7 percent or more
of pertussis cases in large series of hospitalized children
developed CNS complications (Zellweger, 1959), whereas
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the incidence rates of encephalopathy3ranged
from an estimated 0.08 per 1,000 cases in a case series collected
from 1932 to 1946 in Brooklyn, New York (Litvak et al., 1948;
Mortimer, 1988), to 0.8 per 1,000 cases in the National Childhood
Encephalopathy Study (Alderslade, 1981). Current data from the
Supplementary Pertussis Surveillance System (SPSS) of the U.S.
Centers for Disease Control (CDC) indicate that of the 8,682 total
cases reported to the CDC from 1986 to 1988, 0.7 percent were
diagnosed with encephalopathy and 1.8 percent were diagnosed with
seizures (Centers for Disease Control, 1990). The accuracy of these
figures, however, is uncertain because the CDC estimates that only
5 to 10 percent of pertussis cases in the United States during this
time period were captured by SPSS (Centers for Disease Control,
1990).
Nutritional deficiencies seen with pertussis result directly
from the inability of patients to retain feedings. Feeding
precipitates paroxysms of coughing which in turn produces repeated
vomiting (Mortimer, 1988). The combination of the disease and
malnutrition can lead to death.
Descriptive Epidemiology
Ecology of B. pertussis B. pertussis is
transmitted by direct respiratory contact with infected persons in
the catarrhal or early paroxysmal stage of disease (Berkow, 1987).
Humans are the sole host. Indirect transmission by contact with the
organism on fomites or on dust is rare (Mortimer, 1988). Pertussis
is highly infectious; attack rates in nonimmunized populations have
been reported to range from 25 to 50 percent in schools and from 70
to 100 percent in susceptible household contacts (Centers for
Disease Control, 1985; Gordon and Hood, 1951; Kendrick, 1940;
Linnemann, 1979). Epidemiologic and laboratory studies suggest that
natural pertussis infection confers vigorous, long-lasting immunity
(Gordon and Hood, 1951; Huang et al., 1962; Stallybrass, 1931). The
chronic carrier state appears to be extremely rare and is not a
factor in disease transmission (Cherry et al., 1988; Lambert, 1986;
Linnemann et al., 1968). Pertussis is an epidemic disease,
occurring every 2 to 5 years in endemic areas, with an average
interval of 3.3 years (Cherry, 1984). No consistent seasonal
pattern has
3
Encephalopathy as defined by Zellweger (1959) follows two clinical
forms. "The first form begins suddenly with convulsions, followed
by a state of unconsciousness or coma with varying neurological
symptoms. In the second form, the onset is more insidious; the
temperature rises within a few days to a high fever, even to
hyperpyrexia, the patients become progressively somnolent, comatose
and even unconscious. In this form convulsions, as well as other
neurological symptoms, as paresis, hemiplegia, paraplegia, motor
aphasia, and decerebrate rigidity may appear. Exceptionally
pertussis encephalopathy imitates an acrodynia-like picture of a
confused state" (Zellweger and Steinegger, 1950, pp. 381-382).
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been identified (Friedlander, 1925; Kanai, 1980; Luttinger,
1916; Mortimer, 1988; Nelson, 1978).
Distribution by Person Pertussis can occur at any age.
Prior to mass immunization, an estimated 95 percent of people
contracted pertussis during their lifetimes (Gordon and Hood,
1951), with 20 percent of cases seen in children under age 1 year
and 60 percent occurring in children from ages 1 to 4 years
(Luttinger, 1916). After the introduction of widespread
immunization, age-specific attack rates shifted upward. The CDC's
SPSS indicates that for the years 1986 to 1988, 46 percent of cases
in the United States were reported in children less than age 1
year, with approximately 35 percent occurring in children less than
age 6 months. Twenty-one percent of total cases were seen in
children ages 1 to 4 years. Of the remaining cases, 16, 5, and 11
percent occurred in people ages 5 to 9, 10 to 14, and 15 years or
older, respectively (Centers for Disease Control, 1990). It should
be reiterated in reviewing these figures that the SPSS captures
only an estimated 5 to 10 percent of pertussis cases in the United
States (Centers for Disease Control, 1990). In light of the
vagaries of pertussis detection and diagnosis, pertussis mortality
and incidence rates worldwide substantially underestimate the true
magnitude of the disease.
Incidence rates of pertussis are consistently higher in females
than they are in males across all geographic areas and ages, with
the exception of children less that age 1 year. The excess of cases
in females, which has been evident in both the pre- and
postvaccination eras, differs from other communicable diseases of
childhood, which tend to occur more frequently in males (Cherry,
1984; Gordon and Hood, 1951). With respect to race, incidence rates
are similar in whites and nonwhites in the United States (Cherry et
al., 1988).
Mortality rates, like incidence rates, are highest in the first
6 months of life. The case fatality rate for infants less than age
6 months has been reported to be 0.5 percent (Centers for Disease
Control, 1990). Case fatality rates, like attack rates, are
reported to be higher in females than in males. The reasons for
this are not clear (Cherry et al., 1988).
Distribution by Place Pertussis continues to be a major
cause of infant and child mortality in the developing world. World
Health Organization (WHO) data collected in 1983 indicate that
600,000 of the 100 million children born annually in less developed
countries die of pertussis or its complications (Grant, 1986). The
following annual crude incidence rates were reported for 1982: 2 to
2,000 per 100,000 population in the WHO Africa region, <1 to 590
per 100,000 population in the Western Pacific region, and 0.25 to
85 per 100,000 population in the European region (Muller et al.,
1986). The wide ranges in these statistics most likely reflect
differ-
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ences in reporting rates as well as in disease incidence. The
crude incidence rate of pertussis in the United States in 1988 was
estimated to be 1.4 per 100,000 population (Centers for Disease
Control, 1990).
Time Trends Mortality rates from pertussis in the
industrialized world have declined significantly in the twentieth
century. In Great Britain, at the turn of the century,
approximately 1 in 1,000 children under age 15 years died of
pertussis, with mortality rates being significantly higher among
infants less than age 1 year. Rates then began to decline in the
first few decades of the century and, by World War II, were
approximately one-tenth of what they had been 40 years earlier
(Department of Health and Social Security, 1976). Mortality rates
declined even more rapidly in the postwar period, although
epidemics of pertussis continued to occur (Department of Health and
Social Security, 1981; Miller et al., 1982).
Mortality from pertussis in the United States has also declined
in the twentieth century. Mortality rates in the United States,
like those in Great Britain, began to decline in the early decades
of the century, declining more rapidly after World War II
(Mortimer, 1980; Mortimer and Jones, 1979). Incidence rates also
declined, leveling out in the early 1970s. Since then, age-adjusted
incidence rates have fluctuated between 0.5 and 1.5 per 100,000
population (Centers for Disease Control, 1987).
Nature of the Causative Organism, B.
pertussis
B. pertussis is a gram-negative pleomorphic bacillus. The
genus Bordetella contains four species: B. pertussis,
which is the agent responsible for human pertussis; B.
parapertussis, which causes a mild pertussis-like syndrome in
humans; B. bronchiseptica, which produces a respiratory
illness in animals but can also infect humans; and B. avium,
which causes a respiratory illness in birds (Kersters et al., 1984;
Manclark and Cowell, 1984). Kloos and colleagues (1981) reported
that the four species are genetically similar and may be more
appropriately considered as biotypes of the same species. They
further hypothesized that the lack of clinical description of
pertussis prior to the sixteenth century may represent an
adaptation of an earlier variant of B. pertussis from an
animal to the human host (Kloos et al., 1981).
B. pertussis contains many biologically active and
antigenic factors (see Table 2-1). Although the effects of these
various factors following natural infection or injection with
killed B. pertussis bacilli have been examined in a number
of studies in animals, understanding of the organism's biology and
pathogenesis remains incomplete.
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TABLE 2-1 Biologically Active and Antigenic
Components of B. pertussisa
Factor
Location and Structure
Biologic Functions
Agglutinogens
Protein surface antigens; multiple serotypes, some
located in fimbriae (pili)
Provide serologic markers for study of
epidemiologic characteristics of pertussis; may play a role in the
attachment of bacteria to ciliated cells; antibody to agglutinogens
may contribute to protection against infection
Filamentous hemagglutinin (FHA)
A cell surface protein that is a hemagglutinin; it
is liberated into fluid of statically grown broth cultures
Important mediator of attachment of bacteria to
ciliated epithelial cells; antibody to FHA may protect against
infection of ciliated cells
Pertussis toxin (PT), also called
lymphocytosis-promoting factor, leukocytosispromoting factor,
histamine-sensitizing factor, islet-activating protein, and
pertussigen
An envelope protein that is a hemagglutinin; it is
liberated into the fluid of static or submerged cultures;
fivesubunit structure
A toxin with many biologic functions in animal
models, e.g., histamine sensitization, lymphocytosis promotion,
enhancement of insulin secretion, and adjuvant activity; antibody
to PT is protective in intracerebral mouse protection test; it is
probably a major virulence factor
Adenylate cyclase
Enzyme that is liberated into culture
supernatants
Has potential to interfere with phagocyte
function
Heat-labile toxin, also called dermonecrotic
toxin, lethal toxin, or lienotoxin
Heat-labile protein toxin found in the cytoplasmic
fraction of cell lysates
Causes skin necrosis in mice, rabbits, and guinea
pigs and is lethal in mice after intravenous administration
Endotoxin, also called lipopolysaccharide
Envelope toxin
Activities similar to those of endotoxins of other
gram-negative bacteria
Tracheal cytotoxin
Small glycopeptide found in culture
supernatants
Causes ciliostasis and cytopathology of hamster
tracheal epithelial cells in organ culture
Hemolysin
Unknown
Hemolysin-deficient mutant was shown to have
reduced virulence in mice
Outer membrane protein respiratory
infection
Outer membrane of organism
Antibodies to this protein protect mice
against
a Modified
from Cherry et al. (1988) and Mortimer (1988). Reproduced by
permission of Pediatrics.
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B. pertussis Virulence Factors and Pathogenesis of Whooping
Cough
When B. pertussis invades susceptible humans, the
organism adheres to ciliated epithelial cells of the respiratory
tract and multiples there without invading the tissues (Lapin,
1943; Pittman, 1970). Yet, this colonization leads to profound
changes in tissues that persist long after the responsible bacteria
have been cleared. Such observations suggest that a toxin or toxins
from the bacteria play an important part in the pathogenesis of the
syndrome.
Among the putative pertussis toxins, the secreted pertussis
toxin (PT) is currently considered the best candidate as a major
virulence factor (Cherry et al., 1988; Mortimer, 1988; Pittman,
1979, 1984; Weiss and Hewlett, 1986). PT is now believed to be
responsible for many of the characteristic activities attributed in
the past to "toxins" in culture filtrates or cell lysates of B.
pertussis. These include lymphocytosis, which is often seen in
patients with whooping cough, increased sensitivity to shock on
injection of histamine into mice (histamine-sensitizing factor),
and hyperinsulinemia and hypoglycemia (islet-activating protein)
(Pittman, 1984).
PT is a protein composed of five linked subunits (S1, S2, S3,
S4, and S5). The subunits S2 to S5 form a nontoxic unit that binds
to the cell membrane; toxicity is mediated by the subunit S 1,
which acts as an enzyme (Pizza et al., 1989). The activity of
subunit S1 inhibits a subclass of proteins (G proteins) that are
essential for transmission of biochemical messages from receptors
on the cell surface to the intracellular machinery that permits the
cell to function. Genetic engineering has been used to replace one
or two key amino acids within the enzymatically active S1 subunit,
resulting in a stable nontoxic form of PT. Such an agent has the
potential to be used as a safe immunogen (Pizza et al., 1989).
Other toxins have been proposed, but there is less experimental
evidence to support the participation of these other toxins in the
pathogenesis of pertussis. Two forms of the enzyme adenylate
cyclase, one of which is released into culture fluids and the other
of which is intracellular, are associated with B. pertussis
(Confer and Eaton, 1982; Hewlett and Wolff, 1976; Hewlett et al.,
1976; Weiss et al., 1984). The latter can be internalized by
phagocytic cells and inhibit their function through elevation of
intracellular cyclic adenosine monophosphate (Confer and Eaton,
1982). There is a lipopolysaccharide that possesses all of the
usual properties of enterobacterial endotoxins, except that it is
less pyrogenic on a weight basis (Chaby et al., 1979). It is
present in whole-cell vaccines (Cameron, 1988; Pittman, 1984). A
dermonecrotic toxin (Livey and Wardlaw, 1984; Nakase and Endoh,
1986) and a tracheal cytotoxin (Goldman et al., 1982) have been
purified and studied in tissue culture or animals. Adherence of
B. pertussis to respiratory epithelium is required for the
pathogenesis of whooping cough (Pittman, 1970). Adherence appears
to involve a bacterial outer membrane
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protein with a molecular mass of 69 kilodaltons, termed the
69-kD outer membrane protein (Charles et al., 1989; Shahin et al.,
1990). Injection of this protein into mice elicits a protective
antibody response in a respiratory model (Charles et al.,
1989).
Two other bacterial surface structures have been proposed to
play a role in the pathogenesis of whooping cough through the
promotion of adherence to respiratory cilia. These are FHA (Sato et
al., 1983) and serotype-specific agglutinogens (Preston et al.,
1982). Immunization with cellular vaccines raises antibody to both
of these (Pittman, 1984).
Major Milestones in the Development of
Pertussis Vaccines
Whole-Cell Vaccines
When the description of the Bordet-Gengou technique for
isolating the pertussis bacterium was published (Bordet and Gengou,
1906), numerous researchers began to experiment with vaccines from
killed whole-cell B. pertussis. Such vaccines were
developed, and used in children, by Bordet and Gengou in 1912,
Nicolle of the Pasteur Institute in Tunis in 1913, and Madsen of
the Danish State Serum Institute in 1914, among others (Chase,
1982). By 1914, pertussis vaccine was listed in New and
Nonofficial Remedies, a publication of the American Medical
Association (Council on Pharmacy and Chemistry, 1914, 1931).
Kendrick, of the State of Michigan Health Department, further
refined and used whole-cell pertussis vaccines in children
(Kendrick, 1942, 1943; Kendrick and Eldering, 1936, 1939). In 1942,
Kendrick and colleagues combined her improved killed vaccine with
diphtheria and tetanus toxoids to produce the
diphtheria-pertussis-tetanus (DPT)4combination vaccine. In 1944, the
Committee on Infectious Diseases of the American Academy of
Pediatrics suggested routine use of pertussis vaccine and, in 1947,
recommended its use in the form of the DPT combination (American
Academy of Pediatrics, 1944; Cherry, 1984). During the 1940s and
1950s, vaccination of U.S. children against pertussis became a
routine procedure. By the mid-1960s, many states had passed laws
requiring that all children be vaccinated with the DPT vaccine
prior to entry into school (Coulter and Fisher, 1985).
For additional information on the development of pertussis
whole-cell vaccines, see Appendix B, Pertussis and Rubella
Vaccines: A Brief Chronology.
Acellular Vaccines
Acellular pertussis vaccines were developed in Japan, prompted
by ad
4 Throughout
this report, the acronym DPT has been adopted for the triple
vaccine because of its historic usage. It is synonymous with
DTP.
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verse experiences with the whole-cell vaccine. Japan made
pertussis vaccination mandatory in 1948, but it was not until 1950
that nationwide immunization was undertaken, using whole-cell
vaccine (Kanai, 1980). By the early 1970s, the incidence of
pertussis in Japan had fallen so precipitously that some questioned
the need for continued routine immunization against the disease,
especially given the occasional reports of adverse events following
immunization (Kanai, 1980; Public Health Service, 1986). Several
jurisdictions, in fact, abandoned pertussis immunization at about
that time (Public Health Service, 1986). A vaccine injury
compensation system was established in 1970.
Within a 2-month period in 1974-1975, two Japanese infants died
less than 24 hours after receiving the DPT vaccine (Hinman and
Onorato, 1987; Public Health Service, 1986; Sato et al., 1984).
Although investigators concluded that the whole-cell pertussis
component of DPT had not caused the deaths, vaccination policy was
affected by the occurrences. Use of the pertussis vaccine was
suspended temporarily during the investigation, and when its use
was resumed, recommendations were made to raise the age of first
administration from 3 months to 2 years. In addition, the Japanese
Ministry of Health and Welfare established a Pertussis Vaccine
Study Group to facilitate research on an improved vaccine. Clinical
trials of acellular vaccines began in 1979; routine use of the new
vaccines was initiated in 1981 (Public Health Service, 1986).
Two types of acellular pertussis vaccines, the B type and the T
type, are currently manufactured and distributed in Japan. The B
type is made up of lymphocytosis-promoting factor (LPF) and FHA in
approximately equal amounts; the T type (which is used more
frequently) consists of significantly more FHA than LPF and
includes agglutinogens (Hinman and Onorato, 1987). The vaccination
series is begun at age 2 years and consists of three consecutive
doses given at 1-month intervals and a fourth dose given 1 year
later. The T-type vaccine has been evaluated in several preliminary
studies of immunogenicity and toxicity in the United States
(Anderson et al., 1985; Edwards et al., 1986; Lewis et al., 1986;
Pichichero et al., 1987; Rodgers and Badgett, 1985). Trials of the
Japanese vaccines have also been carried out in Sweden (Blackwelder
et al., 1988; Hallander and Mollby, 1988; National Institutes of
Health, 1988). Clinical trials of acellular pertussis vaccines are
in progress in the United States.
Brief History of the Controversy
Pertaining to Adverse Events Following Pertussis Vaccination
Madsen, of the State Serum Institute in Copenhagen, Denmark, was
the first to describe the use of whole-cell pertussis vaccine on a
large scale (Madsen, 1925, 1933). His vaccine successfully
controlled two outbreaks in the Faroe Islands. His 1933 account
reported two deaths within 48 hours
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of immunization, the first published report of serious adverse
effects after pertussis vaccination. In the same year, Sauer of
Northwestern University Medical School in Chicago described minor
reactions to a whole-cell pertussis vaccine being used in the
United States (Sauer, 1933a,b).
In the late 1940s, the first published reports of irreversible
or chronic neurologic damage following vaccination against
pertussis appeared (Brody and Sorley, 1947; Byers and Moll, 1948).
Brody and Sorley reported only one case, but their report led to
the first warnings that pertussis vaccine should not be
administered to those with a known neurologic disorder.
In Britain in 1974, questions about the safety of pertussis
vaccines were widely publicized in the popular press after
newspaper accounts of a study suggesting adverse reactions
(Kulenkampff et al., 1974), and an Association of Parents of
Vaccine Damaged Children was formed (Alderslade et al., 1981).
Between 1974 and 1978, the proportion of British children
vaccinated against pertussis fell from 80 to 30 percent, on
average, dropping as low as 9 percent in some areas (British
Medical Journal, 1981). An epidemic of pertussis subsequently
occurred; between 1977 and 1979, more than 100,000 cases and 36
deaths were reported (Koplan and Hinman, 1987).
The controversy over the safety of pertussis vaccines reached
the U.S. public in 1982, when the television program, "DPT: Vaccine
Roulette," was first broadcast by NBC affiliate WRC-TV in
Washington, D.C. The program depicted children with severe injury
allegedly caused by pertussis vaccines (Griffith, 1989; Koplan and
Hinman, 1987). Following broadcast of that program, an advocacy
group, Dissatisfied Parents Together, was formed in the United
States. Its members called for research toward a safer pertussis
vaccine and mandatory reporting of adverse reactions. Some members
of the group called for a cessation of the use of whole-cell
vaccines (Coulter and Fisher, 1985; Koplan and Hinman, 1987).
For additional information on the controversy surrounding
pertussis wholecell vaccines, see Appendix B, Pertussis and Rubella
Vaccines: A Brief Chronology.
RUBELLA VACCINES
Epidemiology of the Disease
Rubella
Clinical Description
Rubella is commonly a mild disease; it afflicts children and
young adults. It is characterized by an erythematous,
maculopapular, discrete rash; postauricular and suboccipital
lymphadenopathy; and minimal fever (American Academy of Pediatrics,
1986). The disease is caused by an RNA virus belonging to the
togavirus family. It can be transmitted transplacentally to the
fetus, sometimes with devastating results (Berkow, 1987).
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(Berkow, 1987; Schlossberg and Topolsky, 1977), serious
complications are few and rare. Encephalitis, occasionally
resulting in death, and thrombocytopenia have been reported (Morse
et al., 1966; Sherman et al., 1965), as have chronic arthralgia,
arthritis, and polyneuritis (Ogra and Herd, 1971; Ogra et al.,
1975; Schaffner et al., 1974). The latter vary in frequency with
age and sex, being greatest in adult females and least in
prepubertal children. Complications of congenital rubella are
numerous and profound (see the section Clinical Description). A
rare late syndrome of congenital rubella is rubella panencephalitis
(Townsend et al., 1975; Weil et al., 1975).
Descriptive Epidemiology
Ecology of the Rubella Virus Rubella virus is spread by
airborne droplet nuclei or by close contact. Rubella does not
appear to be as contagious as certain other common viral childhood
diseases are, as indicated by seroepidemiologic studies showing
that even after explosive outbreaks, 10 to 20 percent of young
adults may remain susceptible (Plotkin, 1988). However, under
crowded conditions where the proportion of susceptible individuals
is high, rubella can be highly infective (Brody, 1966; Grayston et
al., 1972; Halstead et al., 1969). Exposure to rubella disease is
believed to confer life-long immunity (Berkow, 1987).
Humans are the sole host of the rubella virus, and subclinical
cases are common. Virus has been shown to be present in
nasopharyngeal secretions from 7 days before to 14 days after onset
of the rash in postnatal cases. Infants with congenital rubella can
shed the virus in nasopharyngeal secretions and urine for a year or
more after birth (Cooper et al., 1965; Scheie et al., 1967).
Distribution by Person Age at the time of infection
varies geographically for postnatal rubella. In areas where living
conditions are crowded, rubella tends to occur at an early age; in
areas that are less crowded or that are isolated, such as island
nations, rubella tends to occur at a later age, with a significant
number of people remaining seronegative into young adulthood
(Ingalls, 1967). Congenital rubella affects more infants of younger
mothers than infants of older mothers, perhaps because the former
are more likely to be seronegative (Plotkin, 1988).
Distribution by Place Rubella occurs worldwide (Assaad
and LjungarsEsteves, 1985; Cockburn, 1969). The disease is probably
more common in areas where living conditions are crowded, although
accurate incidence rates are difficult to obtain in the absence of
seroepidemiologic confirmation, because many childhood cases are
asymptomatic and therefore go undetected (Plotkin, 1988).
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Little is known about the geographic distribution of congenital
rubella in much of the developing world (Mingle, 1985; Seth et al.,
1985), although incidence rates tend to vary at a given time
according to the number of susceptible (seronegative) adult women
and the presence of the virus (Plotkin, 1988). In the United
States, prior to widespread vaccination, incidence rates of
congenital rubella syndrome in nonepidemic years averaged 4 to 8
per 10,000 pregnancies (Williams and Preblud, 1984). A similar rate
of 4.6 per 10,000 births was observed in the United Kingdom
(Peckham, 1985).
Time Trends Prior to mass immunization, rubella was both
an endemic and an epidemic disease in the United States. The
disease occurred year-round, but tended to peak in the
spring. Epidemics occurred at 7-year intervals (Witte et al.,
1969). With the advent of mass immunization, rubella incidence
rates declined by more than 95 percent compared with those in the
prevaccination era, although isolated epidemics in susceptible
groups have continued to occur (Cherry et al., 1988).
Nature of the Rubella Virus
The initial realization of the teratogenic potential of maternal
rubella in the early 1940s spurred attempts to isolate and
characterize the responsible agent. It was not until 1962, however,
that Weller and Neva (1962) and Parkman and colleagues (1962)
independently isolated the rubella virus; the latter group used the
technique of interference with the growth of enteroviruses in
African green monkey kidney tissue culture that was to become a
standard method for virus isolation (Plotkin, 1988).
The rubella virus was subsequently found to be a cubical,
medium-sized, lipid-enveloped virus, ultimately classified in the
togavirus family. The virus, in addition to its lipid envelope, is
composed of three proteins, two in the envelope and one in the core
(Pettersson et al., 1985). Upon infection, it replicates in the
nasopharynx, from which it spreads to the local lymph nodes. During
viremia, the placenta can be infected, leading to introduction of
the virus into the fetal bloodstream and to the subsequent
disruption of organogenesis (Alford et al., 1964; Naeye and Blanc,
1965; Plotkin et al., 1965a; Tondury and Smith, 1965). The exact
pathologic mechanisms underlying the disruption of organogenesis
are unclear (Plotkin, 1988), but they may, in part, involve
inhibition of fetal cell mitosis by a soluble protein inhibitor
(Naeye and Blanc, 1965; Plotkin and Vaheri, 1967; Plotkin et al.,
1965a).
Major Milestones in the Development of
Rubella Vaccines
In 1938, Hiro and Tasaka succeeded in transmitting rubella by
inoculating healthy nonimmune children with filtrates taken from
children with
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Page 23
active cases of rubella. The causative agent remained
unidentified (Chase, 1982). By 1948, Burnet and colleagues were
using gamma globulin from patients with rubella to confer
short-term passive immunity on pregnant women recently exposed to
rubella (Chase, 1982). The practice became common in a number of
industrialized countries.
In the early 1960s, the rubella virus was isolated by Weller and
colleagues at the Harvard School of Public Health (Weller and Neva,
1962) and by Parkman and colleagues at the Walter Reed Army
Institute of Research (Parkman et al., 1962). The rubella epidemic
in Europe and the United States between 1962 and 1965 led to
thousands of cases of congenital rubella syndrome and lent impetus
to the search for a vaccine (Chase, 1982; Plotkin, 1988). Between
1965 and 1967, several vaccines made from attenuated rubella
strains were developed and tested in clinical trials (Plotkin,
1988).
Three rubella vaccines were licensed in the United States in
1969-1970 and became widely used: HPV-77 (high passage virus) grown
in dog kidney, HPV-77 grown in duck embryo, and Cendehill grown in
rabbit kidney (Plotkin, 1988). A human diploid fibroblast vaccine,
RA 27/3, also developed in the United States in the 1960s, was
first licensed in Europe and came to be used extensively in the
United Kingdom, France, Switzerland, and Italy. It was not licensed
in the United States until 1979. By that time, the manufacturers of
the dog kidney and Cendehill strains had left the U.S. market. In
1979, Merck Sharp & Dohme, the only remaining manufacturer of
the duck embryo vaccine in the United States, began making and
selling RA 27/3 instead. It has been the only rubella vaccine
manufactured or distributed in the United States since that
time.
Although the rates of rubella and congenital rubella syndrome
dropped dramatically after the introduction of rubella vaccines,
medical policymakers in the United States became convinced by the
late 1970s that to eradicate rubella and congenital rubella
syndrome entirely, it would be advisable to vaccinate women of
childbearing years as well as young children (Preblud, 1985;
Tingle, 1990). Recommendations were made that women be vaccinated
for rubella postpartum, and that female medical and health-care
workers be vaccinated. Some institutions began to require such
immunization for female health-care professionals; some
universities also started to require immunization for female
students.
For additional information on the development of rubella
vaccines, see Appendix B, Pertussis and Rubella Vaccines: A Brief
Chronology.
Brief History of the Controversy
Pertaining to Adverse Events Following Rubella Vaccination
Two types of adverse events after rubella immunization have
primarily been reported. Postvaccination neuropathies were observed
in children early in the experience with the vaccine. Between 1970
and 1974, a number of
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Page 24
reports described two temporary conditions that came to be known
as the "arm syndrome" and the "leg syndrome" (or the "catcher's
crouch syndrome") (Gilmartin et al., 1972; Kilroy et al., 1970;
Schaffner et al., 1974). Evidence indicated that these events were
especially likely to occur with the dog kidney vaccine (e.g., Grand
et al., 1972; Kilroy et al., 1970). Such reports contributed to the
decision to license RA 27/3 in the United States and to the
withdrawal of the other vaccine strains from distribution in the
United States and a number of other countries (Plotkin, 1988).
Acute arthralgia and arthritis following vaccination were also
reported in the earliest studies of rubella vaccines (American
Journal of Diseases of Children, 1969; Barnes et al., 1972;
Horstmann et al., 1970; Lerman et al., 1971; Spruance and Smith,
1971). All rubella vaccine strains have been associated, to some
extent, with reactions in the joints. Again, the HPV-77 dog kidney
vaccine appeared to be most often associated with such events
(Barnes et al., 1972; Spruance and Smith, 1971), but other strains,
including RA 27/3, have been implicated as well (Fox et al., 1976;
Freestone et al., 1971; Horstmann et al., 1970; Lerman et al.,
1971; Rowlands and Freestone, 1971; Swartz et al., 1971; Tingle et
al., 1979, 1985, 1986; Weibel et al., 1972). It has been reported
that arthritis, arthralgia, and other joint disorders are observed
with greater frequency after natural rubella infection than after
administration of rubella vaccine (Tingle, 1990).
The incidence of arthritis and arthralgia following rubella
vaccination, as is the case with natural rubella infection, is low
in infants and young children, but is higher and more severe in
adults (Best et al., 1974; Dudgeon et al., 1969; Polk et al.,
1982). There are reports of chronic, severe arthritis and related
conditions in postadolescent women who have received the vaccine
(Tingle et al., 1979, 1985, 1986). Some have charged that results
of prelicensure clinical trials carried out primarily in children
were improperly generalized to adults, leading to the assumption
that the vaccine is safe for adults as well (Hatem, 1990; Tingle,
1990). A randomized, double-blind, placebo-controlled trial of
rubella vaccine and chronic arthritis is currently in progress in
Vancouver, British Columbia, Canada (A. Tingle, British Columbia
Children's Hospital, personal communication, 1991). In
addition, as of April 1991, the CDC is considering issuing a
request for proposals for a study of chronic arthritis following
rubella vaccination that would include detailed laboratory studies
of participants.
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Representative terms from entire chapter:
pertussis vaccine
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