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PRESENTATIONS
Pertussis: Clinical Features and Diagnosis
Clinical Spectrum of Pertussis
Across the Ages
Dr. Jussi Mertsola
Pertussis may be categorized according to stage: the catarrhal
stage, when there is cough, rhinorrhea and possible fever; the paroxysmal
stage, during which the whoop and vomiting after cough occur; and the
convalescent stage, consisting of gradual recovery with possible set-backs.
Complications are most common in infants. In the U.S., 63% of infants
< 6 months of age required hospitalization; complications included
pneumonia (11.8%), seizures (1.4%), and encephalopathy (0.2%), and the
mortality rate was 0.8%(1). In one U.S. study, 98% of infants
who died had pneumonia, and 78% had not been vaccinated(2).
Heininger et al(3) found that in 18% of 51 cases of sudden
infant death syndrome the results of polymerase chain reaction (PCR) testing
were positive for B. pertussis.
In Finland, there were 164 laboratory confirmed pertussis
cases admitted to university hospitals in the 1990s. About 70% were <
4 months old, 22% were admitted to the intensive care unit (ICU), and
8% required assisted ventilation. Comparison of pertussis symptoms in
immunized and unimmunized children indicated that the whoop was present
in 39% of immunized as compared with 56% of unimmunized children, vomiting
in 49% versus 65%, and apnea in 8% versus 15%(4).
There is good evidence that vaccine efficacy decreases
with time, possibly from 100% at 1 year down to 46% at 7 years(5).
This is why there was a trend toward increased pertussis incidence among
older children, adolescents, and adults in the 1990s. In Finland, the
whole cell pertussis vaccine has been available since 1952 and is given
at 3, 4, 5, and 24 months, with about 98% coverage. In the 1990s there
was a 5-fold increase in the incidence of pertussis among infants, who
get the disease mainly from adolescents and adults. In 1999, 29% of laboratory
confirmed cases in Finland were aged 20 years or older. Symptoms in adolescents
and adults have included paroxysms (83% and 87% respectively), whoop (30%
and 33%), vomiting (45% and 41%), and apnea (19% and 37%)(6).
The State of the Art in Diagnosis of Pertussis: the
Positive Predictive Value of Symptoms in Children, Adolescents and Adults,
and Laboratory Confirmation
Dr. Kathryn Edwards
Diagnostic methods for B. pertussis consist of direct
detection, i.e. culture, direct fluorescent antibody (DFA) testing, PCR,
and indirect detection, i.e. serologic methods using paired sera (from
early and later in the course of the illness), a single elevated antibody
titre, or high titres in family members. In the past, culture was the
gold standard, but many factors influence its sensitivity. DFA provides
rapid results, but it has low sensitivity. PCR methods are not consistent
across laboratories in terms of sample preparation, primer selection,
detection systems and selection of controls. Enzyme linked immunosorbent
assay (ELISA) is the basis for serologic methods.
Validation of PCR against serology, culture and symptoms
was carried out by Heininger et al(7) in a large pertussis
vaccine efficacy trial (among children) in Germany. Using a positive serologic
result for B. pertussis as the standard, the overall sensitivity
of PCR was found to be 61% and the specificity 88%; PCR was more sensitive
than culture. Comparison of PCR results and clinical symptoms revealed
that duration of cough, presence of paroxysms, whooping and/or vomiting,
and clinical diagnosis of probable or definite pertussis were all significantly
less pronounced in children with negative PCR as compared with positive
PCR results. In a community-based study of the prevalence of pertussis
among 442 adolescents and adults it was found that 20% had either laboratory
confirmed pertussis or laboratory evidence of pertussis, the latter based
primarily on serologic criteria(8). The use of paired serum
samples may be problematic, in that the specimen from the acute stage
is often obtained late; use of a single specimen relies on cut-off levels
that may be arbitrary. Information on levels of antibody to pertussis
antigens in a large sample of the general population could be used as
age-specific reference values for serologic diagnosis. The CDC has carried
out such a survey to determine these levels.
Epidemiology
Epidemiology of Pertussis in Canada
Dr. Eleni Galanis
As measured from data obtained from the National Disease
Reporting System and the Canadian Institute for Health Information, the
incidence of pertussis in Canada has increased since the beginning of
the 1990s, with peaks every 4 years. The average number of reported cases
across Canada in the 1990s was 6,000 or 10 to 35 per 100,000 per year,
the highest incidence being found among infants < 1 year of age and
the second highest currently among children aged 10 to 14. Possible reasons
for the increasing incidence are
- a change in circulating strains of B. pertussis
- waning vaccine immunity
- a decrease in vaccination coverage
- low efficacy of the whole cell vaccine
- increased awareness and reporting.
The stable or decreasing hospital separation rates in all
age groups during the same period suggests that at least part of the increase
in pertussis incidence is due to increased awareness and reporting of
the disease. Not all provinces/territories reported an increased incidence
in the early 1990s, but in all jurisdictions there were large pertussis
outbreaks during different years; this may have led to an overall increase
in pertussis incidence in Canada.
With respect to the acellular vaccine, introduced in 1997,
data from British Columbia, Alberta, Saskatchewan and Ontario show a positive
impact, as illustrated by a decreasing incidence since 1998 among 1 to
6-year-olds as compared with infants < 1 year and 7 to 9-year-olds;
the dip in 2000 among 7- year-olds (2 years after their booster dose of
acellular vaccine); and the fact that the lowest incidence is in the cohort
that has received the most doses of the new vaccine.
Epidemiology of Pertussis in
British Columbia
Dr. Danuta Skowronski
In British Columbia, the gradual increase in reported pertussis
since the 1990s has been accompanied by outbreaks of the disease occurring
in 1990, 1993, 1996 and 2000, each with a higher peak incidence than the
previous outbreak. In 1990, the highest proportion of cases occurred in
children < 5 years of age; in 1993, the pattern was similar, but the
proportion among 5 to 9-year-olds had increased substantially; in 1996,
there were further increases in this age group and also among 10 to 14-year-olds;
and by 2000, the largest proportion occurred among 10 to 14-year-olds.
In 2000, both the proportion of pertussis cases reported and the incidence
were greater among 10 to 14-year-olds than among infants or preschool
children.
Although requests for laboratory confirmation of pertussis
rose during 2000 in the 10-14 year age group, so too did the proportion
of positive test results, suggesting that increased awareness and indiscriminate
laboratory requests were not responsible for the greater incidence of
disease. Neither is PCR testing likely to be the sole reason for recent
trends: even though this laboratory method increased the proportion of
positive results across all age groups, the greatest proportion by either
culture or PCR was reported among pre-teens and teens. The protective
effect of pertussis immunization wanes with time, and individuals aged
10 to 14 might be expected to be more vulnerable to infection than younger
children. However, the increasing rates in the same age group over each
outbreak, together with a declining incidence after age 12 during 2000,
argue against waning immunity as an explanation for the epidemiologic
pattern. On the other hand, a vaccine that was suboptimal in its efficacy
10 years ago would be expressed through a persistent cohort effect such
as the one noted.
The results of introducing the more efficacious acellular
vaccine in 1997 have been beneficial. The incidence of pertussis among
infants and preschool children fell appreciably between 1996 and 2000,
as did rates of hospitalization (by half among infants and one-quarter
among preschool children).
Epidemiology of Pertussis in the U.S
Dr. Trudy Murphy
The National Notifiable Diseases Surveillance System in
the U.S. is a passive system that has been in operation since the 1960s,
in which individual States send data on confirmed and probable cases of
notifiable disease, including pertussis, to the Centers for Disease Control
and Prevention (CDC). A confirmed case is defined as one in which B.
pertussis has been isolated, or as a clinical case with either a positive
PCR result or a link with a laboratory confirmed case; a probable (clinical)
case is defined as 14 days or more of cough with paroxysms, whoop or vomiting,
with no other cause.
From the early 1990s there has been an increase in the
number of reported pertussis cases, ranging from < 5,000 cases per
year in 1990 to 7,867 cases in 2000, and yet rates of immunization -
vaccine given at 2, 4, 6, 15 to 18 months and 4 to 5 years - have
remained high, in the 90%+ range for at least three doses of either acellular
or whole cell vaccine. As well, the number of deaths (which occur predominantly
in infants) has been increasing since the late 1990s.
The acellular pertussis vaccine has been available for
the fourth and fifth doses in the immunization program since 1992 and
for the primary series since 1996. Overall, the incidence or reported
number of cases has remained fairly stable among 1 to 4 and 5 to 9-year-old
children. Among infants 4 to 11 months who received at least two doses
of the acellular vaccine there was a levelling off in rates from the mid-1990s,
whereas among younger infants with fewer doses this occurred later. The
incidence of reported cases among 10 to 19-year-olds and, to a lesser
degree, among adults aged 20+ has increased during the 1990s. It is unclear
how much of the increase among adolescents represents a real increase
or improvements in recognition, diagnosis and reporting.
The APERT Study
Dr. Joel Ward
The APERT study(9), sponsored by the National
Institutes of Health, was a prospective, randomized controlled trial (double
blind) that was carried out at eight sites in the U.S. to assess the incidence
and clinical spectrum of pertussis in adolescents and adults as well as
the efficacy and safety of the acellular vaccine in these individuals.
One dose of vaccine was administered to 2,781 subjects aged 15 to 65,
recruited between 1997 and 1999. Acellular pertussis vaccine was given
in the experimental group and hepatitis A in the control group. All subjects
were prospectively followed and contacted every 2 weeks for 2 years. If
they reported a cough of 5 days' duration or longer this was evaluated
clinically and by culture, PCR, and serologic testing (acute versus convalescent
specimens). Each subject provided three to 10 blood specimens for serologic
evaluation during the study to detect asymptomatic infections.
Cough illness was found to be very common in both groups
(about half of all subjects reported a cough lasting 5 or more days per
year), with a mean duration of 24.4 days. There was no significant difference
between the vaccine groups in incidence of cough illness. There were 10
cases of well-confirmed pertussis detected during the trial, as determined
by positive results on culture or PCR or by increases in antibody titres;
all but one of the cases occurred in the control group. The overall efficacy
of the pertussis vaccine was estimated to be 92%. Pertussis cases as a
proportion of reported cough illness increased significantly the longer
the duration of cough, i.e. the longer the cough continued the higher
the proportion of pertussis cases. Risk factors for pertussis were young
age (< 30 years) and duration of cough. Culture and PCR were relatively
insensitive in diagnosis, even early in the illness at day 5 of cough.
The incidence of disease as determined in the unimmunized
controls was 4 cases per 1,000 subjects per year. This represents up to
1 million cases per year in older individuals in the U.S. No serious adverse
events from the vaccine were reported, although local reactions were experienced,
more commonly by women than men.
Epidemiology of Pertussis in France
Dr. Nicole Guiso
In France, the whole cell pertussis vaccine, combined with
diphtheria and tetanus toxoid and polio vaccine, has been in use since
1966, given at 3, 4, and 5 months with a booster at 16 to 18 months; Haemophilus
influenzae type B vaccine was added in 1995. In 1985, only 86 cases
of pertussis were reported, therefore the disease was discontinued as
a notifiable disease and surveillance ceased. In 1991, however, a study
carried out in a pediatric hospital reported that the number of infants
hospitalized for pertussis had increased and that there was a change towards
adult-infant rather than child-child transmission(10).
In a subsequent national study(11), in 1993-1994,
involving 22 pediatric hospitals (20% of the total number in France),
316 index cases were reported, of which 204 (65%) were aged < 1 year
and 99 (33%) were < 3 months. Of 314 index cases, 230 (73%) had not
been vaccinated, 98 because they were < 3 months old. The resurgence
of pertussis was not felt to be due to decreased vaccination coverage
or vaccine efficacy. Since 1996, surveillance carried out in 43 pediatric
hospitals across France has shown similar trends. In 1998, the immunization
schedule was changed to a primary series of whole cell vaccine at 2, 3,
and 4 months, a first booster dose of acellular vaccine at 16 to 18 months,
and an additional booster dose of acellular vaccine at age 11 to 13 years.
A 1999 study to estimate the incidence of pertussis in
adults recruited 217 patients aged ³ 18 years who complained of cough
lasting > 7 but < 31 days(12). A diagnosis of pertussis
was confirmed by culture, PCR or serologic detection of increased or decreased
anti-pertussis toxin IgG (by a factor of at least 2) between acute and
convalescent serum samples. A total of 70 confirmed cases were found (32%),
for an estimated incidence of 884 cases per 100,000. Antibiotic treatment
did not modify the duration of cough.
Booster vaccination doses given to adolescents and adults
regularly throughout life would be the ideal strategy for reducing the
burden of pertussis, but this is not feasible for a number of reasons.
Vaccination of targeted groups, such as adolescents, adults in contact
with infants, and vulnerable adults with other health problems, is more
likely to succeed.
Epidemiology of Pertussis in the U.K.
Dr. Natasha Crowcroft
In the U.K., a whole cell pertussis vaccine is given in
a combined vaccine at 2, 3, and 4 months, and since 2001 a booster dose
of acellular vaccine has been added at age 3.5 to 5 years. Although there
was widespread concern among the public about the adverse effects of the
vaccine in the late 1970s, vaccination coverage has since recovered and
has been over 90% for the last decade. The last epidemic occurred in 1997,
when 2,989 cases were reported; in 2000 there was an all-time low of 712
cases. The proportion of cases among infants < 3 months increased during
the 1990s. The number of deaths observed varies according to the data
source but has been estimated at 9 per year from 1994 to 1999.
It is believed that the disease is substantially under-reported
- for instance, there are two to three hospital admissions for pertussis
for every one case reported - thus enhanced surveillance and special
studies are needed to improve data collection. A community study conducted
in 1996-97 investigated patients (age range 5-92) who presented with acute
tracheitis or spasmodic cough of > 3 weeks' duration(13).
Of 356 such patients, 58 were identified as having serologic and/or bacteriologic
evidence of pertussis, 32 (55%) of whom were known to have been fully
vaccinated. This is equivalent to an incidence rate of 330 cases per 100,000
per year. (The official notification rate for the period under study was
< 4 per 100,000.) Of those aged 5 to 14 years, 45% had evidence of
recent pertussis infection, and of those 15 to 44 years old the proportion
was 28%. In a further study, carried out in a pediatric ICU, it was found
that 25 of 127 infants (20%) admitted had pertussis, only 3% of whom had
been suspected of having the disease(14). In 44% of cases the
parents were responsible for transmitting the infection, and in 32% it
was a sibling. Taken together, these results indicate that the pertussis
notification rate is a vast underestimate, and that older children and
adults are becoming infected and passing the infection on to infants.
Epidemiology of Pertussis in Australia
Dr. Peter McIntyre
In Australia, there has been an increase in the pertussis
notification rate from the early 1990s to the present, as recorded by
the National Notifiable Disease Surveillance Scheme. The last epidemic
occurred in 1997, when the incidence rate reached almost 60 cases per
100,000 population.
With regard to the burden of disease, in a study of 140
infants hospitalized for pertussis in the year 2001 through the Australian
Paediatric Surveillance Unit, the average hospital stay was 8 days, 18%
required ICU admission, and 3% died(15). Aboriginal babies
were over-represented. In a group of adults with reported pertussis(16),
the median duration of cough was 60 days, median number of visits to the
general practitioner 3.7, and the median number of days in work lost was
4 (equivalent to 15,000 lost work days overall in Australia). With regard
to deaths, the annual rate rose sharply from 1986-95 to 1996-2002. From
1993 to 2001 there were 16 deaths, for an estimated annual mortality rate
of 0.70 per 100,000 (as compared with 0.60 in the U.K. during 1994-99
and 0.32 in the U.S. during 1997-2000).
The proportion of reported cases in which serologic results
were positive has increased during the 1990s (New South Wales data). Clinical
diagnosis is much more common in children < 5 years, whereas in those
aged > 5, serologic methods have a greater impact on the number diagnosed.
Laboratory and notification studies have indicated that symptoms of pertussis
in adults match the finding of high whole cell antibody levels(17).
A primary series of pertussis vaccine is given at 2, 4,
and 6 months and boosters at 18 months and 4 to 5 years. Immunization
with acellular vaccine has been funded for the primary series since 1999
and for the booster doses since 1998. Hospitalization data for 2001 show
that more than a third of cases occur before 6 weeks of age and more than
a half before 8 weeks, i.e. in unimmunized infants. Since the introduction
of the preschool booster dose in 1995, 5 to 9-year-old children showed
a decline in notification rates after the 1997 epidemic, close to the
rates for 1 to 4-year-olds, whereas since 1999 and for the first time
in Australia the notification rate among 10 to 14-year-olds has become
higher than among infants. Possible options to address the high incidence
rates among adolescents and the increasing number of infant deaths are
to eliminate the fourth (18 month) booster dose so that the first dose
after the 2, 4, 6 months primary series is at 4 years, but introduce an
adolescent booster; and to encourage pertussis immunization in mothers,
and possibly fathers, at or shortly after the birth of a baby (“cocooning”).
Molecular Surveillance of Pertussis
Dr. Mark Peppler
Molecular surveillance is an essential tool to determine
trends in strain types and their relation with disease and vaccines, for
example, whether the use of vaccines over time leads to the development
of resistant organisms. Three methods of molecular surveillance are serotyping
of isolates using monoclonal antibody to fimbrial antigens; pulsed-field
gel electrophoresis (PFGE), used to generate a genomic fingerprint of
an isolate; and gene typing by PCR, particularly on pertussis toxin S1
subunit and pertactin.
There are two types of fimbriae produced by B. pertussis,
Fim2 and Fim3, and isolates may express one or the other, or a combination
of both, on their surface. There are some problems with the expression
of fimbriae in culture, but they are an important antigenic marker: in
the past, vaccine has had to be modified to address the type of fimbriae
produced by circulating strains of B. pertussis. PFGE is used to
separate genomic DNA fragments that can vary in size from 50 to 200,000
kilobases. The technique was used to analyze 3,700 isolates from Alberta
and Quebec between 1985 and 1994. On the basis of the pulsed field results,
98 different patterns were identified, of which 80% were represented by
15 different types. Although PFGE showed that the most common strains
were different in the two provinces (strains designated 1 and 2 in Alberta,
strains 1 and 3 in Quebec), it cannot define the characteristics of the
strains. Information from gene typing must be added to explore these characteristics.
Pertactin and pertussis toxin S1 subunit are the genes
that have been investigated by gene typing in relation to virulence. Of
the top 30 PFGE types from Alberta and Quebec, estimated numbers and proportions
of the old and new pertactin and pertussis toxin combinations show that
47% overall represented new types, 36% represented old types, and 17%
were in transition. Thus, in Alberta and Quebec at least, there is a trend
away from the old vaccine types, although it is debatable whether this
is a result of vaccine pressure.
Immunization
Pertussis Schedule in the U.K.
Dr. Natasha S. Crowcroft
Children in the U.K. are given the whole cell pertussis
vaccine in a combined form, DTwP-Hib, with meningococcus C and oral poliovirus
vaccine (OPV) at 2, 3, and 4 months, and a booster dose of acellular pertussis
vaccine, DTaP, at the age of 3.5 to 5 years (with MMR and OPV). Before
1990, the primary vaccine schedule was 3, 5, and 9 to 10 months. The new
“accelerated” schedule was introduced in the interests of increasing
coverage and reducing adverse events.
The preschool booster dose was included from 2001 onward
because of evidence of continuing hospitalizations and deaths in young
children. The decision to opt for a 4-year rather than a 15-year booster
was based on a modelling (dynamic) exercise, whereby the cost-benefits
of the two interventions were compared using a variety of assumptions
about direct and indirect costs, vaccine efficacy, herd immunity, incidence,
hospitalization data and deaths. It was felt that if indirect protection
through herd immunity was more than 60% to 70% then a 15-year booster
would be the appropriate choice; when indirect protection is low, then
the booster dose is more beneficial at 4 years. The effects of the booster
dose at 4 years will be monitored, and if necessary that decision will
be revisited.
Pertussis Schedule in France
Dr. Gaston De Serres (on behalf of
Dr. Nicole Guiso)
A whole cell pertussis vaccine is used in France. In 1998
the schedule was switched from a primary series at 3, 4, and 5 months
with a booster between 16 and 18 months to the primary series being given
at 2, 3, and 4 months, a booster dose of acellular vaccine at 16 to 18
months and a second acellular booster dose at 11 to 13 years. Vaccine
coverage in infants is 96% and the efficacy is 94%.
Pertussis Schedule in Sweden
Dr. Patrick Olin
When the whole cell vaccine used in Sweden lost its potency
in the 1970s, routine vaccination of infants against pertussis was discontinued.
This was followed by a resurgence of the disease in the country. The current
schedule for immunization against pertussis consists of three doses in
infancy of DTaP-Hib-polio at 3, 5 and 12 months (the third administered
as a matter of policy after at least a 6 months' interval), and a
late fourth dose at 6 to 10 years of age. It is felt that there is a better
antibody response if the interval between the first two doses is 2 months
rather than 1 month. There has been high vaccination coverage, at about
98%, for the first three doses, and a dramatic reduction in the number
of pertussis cases since acellular vaccination programs began. The counties
in Sweden are using a variety of different acellular vaccines, and this
makes surveillance and estimation of efficacy problematic.
Perspectives on the Immune Response to Acellular Pertussis
Vaccines, Including Cell- Mediated Immunity
Dr. Fred Zepp
The usefulness of a vaccine may be gauged by its clinical
efficacy, the generation of antibody responses to it, and the cell-mediated
immune response, achieved primarily through T cell helpers and/or cytotoxic
T cells. Modern vaccine development strongly concentrates on the interaction
of the various components of the human immune system (mainly T cells,
B cells and antigen presenting cells). The antigen-presenting cells (i.e.
dendritic cells, B cells) present antigen (e.g. vaccine antigen) to T
cells. Depending on the type of antigen and the antigen- presenting cell,
different patterns of T cell function will be activated, leading to the
recruitment of various other T cells having helper, suppressor and cytotoxic
functions. These activated cells then produce cytokines (various interleukins
and gamma interferon) that further amplify T cell reactivity, activate
macrophages, facilitate immunoglobulin production, or enhance the action
of cytotoxic T cells (killer cells).
To explore cell-mediated immunity in the laboratory, T
cells are cultured from peripheral blood and then challenged with the
antigens of interest. In response, the T cells proliferate and produce
cytokines. The cytokine production pattern of T cells can be measured
by means of ELIspot analysis, ELISA or RT-PCR (reverse transcriptase PCR).
These laboratory studies have shown that unvaccinated infants do not have
specific antibodies to pertussis antigens(18). After the primary
immunization course the infants develop antibodies, which wane through
the second year of life. Booster vaccination reactivates B cell memory
and leads again to an increased concentration of pertussis-specific antibody.
The antigen-specific proliferative T cell response increases with the
first dose of vaccine and, in contrast to B cell responses, remains elevated
even during the time when there are low levels of circulating antibodies.
Booster vaccination further potentiates the antigen-specific T cell response.
The findings suggest that pertussis-specific T helper responses control
immunologic memory, thus providing protection between vaccinations. The
T cell response after natural infection is very similar to vaccine induced
responses(19).
Comparison of immune responses in infants to acellular
and whole cell pertussis vaccines shows that acellular vaccines provide
a better, longer lasting cellular immune response than whole cell vaccine.
Overall, they are highly immunogenic for B and T cells; they induce high
concentrations of antigen-specific antibodies and high rates of seroconversion,
as well as long-lasting pertussis-specific T cell responses.
Impact of the Acellular Pertussis Vaccine on Canadian
Children Since 1997-1998
Dr. Gaston De Serres
The estimated efficacy of the adsorbed whole cell pertussis
vaccine used in Canada has ranged between 28% and 60%, whereas that of
three doses of the acellular pertussis vaccine given in clinical trials
was 85%. The proportion of pertussis cases by age during the 1990s, when
the whole cell vaccine was being used, shows a shift in peak incidence,
from the highest incidence among infants in 1990 to a peak among those
aged 3 to 4 years in 1993 and, again, among children approximately 3 years
older than this in 1996. This has been taken to represent a cohort effect
resulting from the lack of protection in a proportion of infants vaccinated
in 1990.
With regard to the acellular vaccine, data from IMPACT (the
pediatric hospital-based surveillance system) for 1990 to 2001 indicate
that, for infants admitted to hospital because of pertussis, the ratio
of those aged < 3 months (i.e. not vaccinated) to those 3 to 5 months
of age did not change after the acellular vaccine had been introduced,
in 1998. However, the ratio of infants < 3 months to infants 6 months
to 1 year (i.e. those who had received three doses of vaccine) did increase
dramatically after 1998. Thus it appears that with the use of the new
acellular vaccine the number of older infants hospitalized has been reduced.
Data from Quebec on the number of pertussis cases reported according to
age also show this change in ratios after 1998. In terms of older children,
the reported rates per 100,000 in Quebec were considerably higher among
3 to 5-year-old children than 9 to 11-year-olds up to about 1997, but
after 1998 the rates tended to converge, and from 2000 onward the rates
among 3 to 5-year-olds have been lower, as would be expected from the
booster dose of acellular pertussis vaccine they received in 1998.
The use of acellular pertussis vaccine has reduced the
risk of pertussis in infants and children. The group protected by this
vaccine will be moving into adolescence in the next few years and may
still be at decreased risk. The group that received only whole cell vaccine
remains vulnerable now and would benefit the most from an adolescent booster
dose of acellular vaccine. This cohort is currently aged from 10 to 17-22
years, depending on the year of introduction in the different provinces.
Efficacy of Acellular Pertussis Vaccines in Infants
and Duration of Protection
Dr. Patrick Olin
Many different types of acellular pertussis vaccine with
from one to five antigen components have been evaluated in efficacy trials
and compared with whole cell vaccines. Although the overall antigen level
may be similar among vaccine types, the amounts of individual antigens
- for instance, pertussis toxoid - vary widely. The conclusions
of a Cochrane review of randomized controlled trials (RCTs) were that
acellular pertussis vaccines with three or more pertussis antigens were
more effective than those with one or two antigens(20); they
were more effective than one whole cell vaccine but less effective than
two others; and they showed fewer adverse effects than whole cell vaccine.
It is important to note that there are a few whole cell vaccines with
high efficacy. The greater efficacy of multicomponent over single component
vaccines has been questioned by some authors, who argue that the result
is an artifact of the serologic criteria used(21).
With regard to duration of protection, active surveillance
in an Italian trial of two types of three-component acellular vaccine
showed no difference between the vaccines during the first 6 years of
life, and it was concluded that efficacy was maintained over 5 or 6 years(22).
In a comparison of a four-component acellular pertussis vaccine and a
whole cell vaccine given at 3, 4.5, 6 and 18 months of age in German trials(23),
overall cough rates were similar in both groups, and the calculated efficacy
over 6 years of follow-up was 89% for the acellular vaccine and 92% for
the whole cell vaccine.
The incidence of pertussis in Sweden rose to high levels
after the discontinuation of routine vaccination in 1979. With the introduction
of acellular pertussis vaccine in 1996 there was a rapid drop in culture-confirmed
cases from 1996 to 1998. Before the vaccine was in use, most of the disease
burden occurred in 2 to 4-year-old children, whereas peaks were evident
in the higher age groups after its introduction. Analysis of vaccine failures
shows that at 6 to 7 years of age there is a clear increase in the number
of failures particularly with the three-component and five-component acellular
vaccines, suggesting that there is waning immunity after the primary dose
and a possible need for a preschool booster dose.
Vaccine Safety: Risk with Multiple Doses of Acellular
Pertussis Vaccine
Dr. Scott Halperin
Although the rate of adverse events during the primary
series of pertussis vaccination does not increase with succeeding doses,
it has been found that the risk of injection site reactions is higher
with subsequent booster doses.
After the booster dose at 18 months, redness, swelling
and tenderness have been found to increase substantially as compared with
reactions to the vaccine in the primary series(24). Systemic
reactions, such as fever, crying, irritability and drowsiness, on the
other hand, tended to decrease with the booster dose. The fifth consecutive
dose, at 5 years of age, resulted in further increases in local reactions
over the 18 month dose, from 35% to 60% of recipients for redness and
18% to 70% for swelling, although there was a reduction in tenderness(25).
A study of 356 children given a variety of vaccine types found that although
five doses of acellular vaccine and five doses of whole cell vaccine resulted
in similar proportions of cases reporting redness at the injection site,
the acellular vaccine gave rise to fewer systemic adverse events(25).
A U.S. study has also shown increased redness and pain with the fifth
dose of a variety of acellular pertussis vaccines(26). Whole
limb swelling after three doses of DTaP has been reported in Germany and
subsequently in a solicited adverse event cohort (2.5%) and an unsolicited
adverse event cohort (0.5%)(27). With regard to adolescent
and adult studies, although redness and swelling occur with administration
of Td vaccine, addition of the acellular pertussis component does not
lead to higher rates of these reactions(28).
The mechanism of injection site events remains unclear,
but may be related to IgG antibody levels and cell-mediated immunity.
Further research is required on this issue as well as on optimal scheduling
and dosage.
Td Coverage in Adolescents and in Adults: Could Pertussis
Piggyback on the Td Booster Program?
Dr. Karen Grimsrud
Acellular pertussis vaccine is currently combined with
tetanus and diphtheria toxoids in the childhood immunization schedule.
One way of increasing protection against pertussis in adolescents and
adults might be to include acellular pertussis vaccine with the Td booster
dose that these groups receive.
A survey of provincial/territorial immunization programs
revealed that all jurisdictions offer publicly funded Td or TdaP between
the ages of 14 and 16 years, either as a school program (10 provinces/
territories) or given primarily by a physician (Ontario), or both. Newfoundland
and Labrador, Nunavut and the Northwest Territories use TdaP. Information
on coverage rates is collected only in Newfoundland/Labrador and Nova
Scotia (95% and 96% respectively); other jurisdictions' estimated
coverage ranges from 75% to 95%.
The results of two surveys (Aventis Pasteur, 2002, and
the BC Centre for Disease Control, 2002) of adult tetanus coverage indicate
that an estimated 64% of adults had been vaccinated, about half within
the previous 10 years, primarily because of recent injury (64%) or for
anticipated travel (12%). Adults received information about immunization
from the media (51%) and their family doctor (43%), and 92% agreed that
they would be vaccinated if this was recommended by their doctor. Other
factors likely to influence their decision were knowledge about the severity
of the disease in adulthood, and exposure and transmission patterns; the
low risk of side effects of the vaccine; the protection it would afford
young infants with whom they might be in contact; and recommendation by
a doctor or public health nurse.
Provision of a booster dose of acelullar pertussis vaccine,
therefore, would fit well with the usual Td booster dose in adolescence
(and in some jurisdictions already does). In adults, uptake could be increased
by public awareness through the media, encouraging physicians to recommend
and provide vaccine, and offering vaccine during routine contact with
public health, e.g. during infant immunization.
The Newfoundland Experience in Implementing the Adolescent
Program
Ms. Cathy O'Keefe
Because of the recommendation of the National Advisory
Committee on Immunization (NACI) supporting adolescent acellular pertussis
vaccination and the apparent shift to older age groups of reported pertussis
cases, Newfoundland and Labrador introduced TdaP into its immunization
program for grade 9 children in 1999-2000. Since 1999, 18,000 have been
immunized, for an overall rate of coverage of 95%.
A survey of public health nurses (n = 82) in 2000
revealed that 67 (82%) had previous experience with the TdP program and
67 had administered 25 or more doses. In 2002, seven communicable disease
coordinators, with input from public health nurses, reported that most
of the staff were pleased with the information materials on TdaP provided
for parents and that the post-immunization tear-off sheet was useful.
It was felt that better communication, for example, through the media,
would have helped in implementing the program in the community. Experienced
nurses reported spending more time in preparing information in the first,
but not subsequent, years of the program; they also needed to explain
the program to other health care professionals.
The adverse effects of the vaccine have consisted of two
official reports of adenopathy, which were deemed not to be associated
with the vaccine, seven official reports of swelling and discomfort at
the injection site, and one sterile abscess.
Since the number of pertussis cases reported has decreased
from the peak incidence in 1994, it is difficult to demonstrate any effect
of the new program at this time. Enhanced surveillance of pertussis will
continue, with review particularly once the cohort immunized with acellular
pertussis vaccine during childhood reaches the age of 15.
Various Strategies for Adolescent and Adult Immunization
Dr. Scott Halperin
With the increased incidence of pertussis among older children
and adults in many jurisdictions, the goal of pertussis control -
to reduce its incidence and severe morbidity among young children -
as articulated by NACI(29) may need to be revised. The current
immunization strategy does control the disease in young children but does
not address the problem in older age groups and in unimmunized infants
< 2 months of age.
An alternative strategy is to provide universal immunization
for adolescents and adults. Ideally, this would not only reduce morbidity
in these age groups but also develop herd immunity and reduce transmission
to young infants. Problematic areas with this strategy are the appropriate
timing of the immunization, the lack of a monovalent acellular pertussis
vaccine, and the safety of administering a sixth dose of the vaccine.
Selective immunization aimed at protecting very young infants
would target pregnant women, close contacts of newborns, and health care
and child care workers. The challenge associated with vaccinating pregnant
women is that the safety of acellular pertussis vaccine in pregnancy is
unknown, as is the duration of protection and the effect of women's
increased antibody levels on their infants' immune
response to subsequent vaccination. Targeting close contacts of newborns,
or “cocooning”, may not be easy to implement, particularly as
the target group would be difficult to define. Protection of health care
and child care workers carried out to benefit young infants and children
might run into objections to mandatory immunization from organized labour,
particularly as there are few data to support such a move.
In summary, there are many unknown variables in the choice
of a different immunization strategy. It has to be decided which are the
most important variables requiring further information before the choice
can be made.
Cost Benefit of Adolescent and
Adult Immunization
Dr. Philippe De Wals
There have been a number of studies to evaluate the economic
effect or cost-benefit of the new acellular pertussis vaccine in Canada.
The most recent one, by Hemels et al, modelled the epidemiologic and economic
consequences of an additional booster dose of acellular pertussis vaccine
for adolescents in Ontario(30).
The model followed a cohort of 144,000 adolescents aged
12, who were given a booster dose of acellular pertussis vaccine (combined
with diphtheria and tetanus toxoids) at the same time as hepatitis B vaccine
and were followed over the course of the next 10 years. The current practice
is to give three doses of hepatitis B vaccine at the age of 12 years and
diphtheria-tetanus vaccine at the age of 14 years. All subjects had received
five doses of whole cell pertussis vaccine in childhood. Estimates of
the burden of disease were taken from Canadian studies carried out during
1994 to 1998. An under-reporting factor of 9 was used. Productivity losses
were given as an average of 5 days' work lost by parents of hospitalized
children and 8 hours of work lost by parents of non-hospitalized children.
Vaccine efficacy was assumed to be 85% over 10 years, and program coverage
was predicted to be 95%.
From the Ministry of Health perspective, it was found that
the new program would result in a yearly additional cost of $0.20 per
child and a cost of $62.40 per pertussis case avoided. The overall outcome
in terms of vaccine purchase was an estimated increase in costs of $2.1
million. However, there was a reduction in the costs associated with vaccine
administration (-$1.1 million), disease burden (-$0.7 million)
and productivity lost (-$2.5), resulting in a net saving of $2.3
million from a societal perspective; 4,500 cases of pertussis would be
prevented.
The study methodology had many problems, and it appears
that a new cost-effectiveness analysis should be done. Among other problems,
the model underlying the study described is a linear, deterministic one
that takes no account of the cyclical nature of pertussis, the possible
indirect effect of the vaccine in reducing transmission, or the waning
of immunity after vaccination. A dynamic model might better mimic the
long-term epidemiology of the disease and evaluate the economic consequences
of adolescent vaccination.
Expected Impact of the Different Strategies to Immunize
Adolescents and Adults: Mathematical Approach
Dr. Babak Pourbohloui
The dramatic recent increase in reported cases of pertussis
in Quebec along with the increased incidence of the disease among adults
prompted a mathematical modelling approach to assess different immunization
strategies for adults and adolescents. It was decided to start the investigation
by looking at the pre-vaccine era, when the population acquired immunity
through exposure to B. pertussis, and to challenge the standard
assumption that such immunity lasted for 20 years. Data from the pre-vaccine
era indicate that only a small proportion, < 2%, of reported cases
were adults, whereas if acquired immunity lasted for only 20 years there
should be many more adults with symptomatic disease for a second time.
The mathematical model assumes that in the pre-vaccine era
infants are fully susceptible until they become infected, and at the end
of the episode of pertussis they move to the fully protected category.
However, their immunity wanes with time, and they move to a lower level
of immunity in which they are susceptible to boosting by infection; they
lose immunity again and again in this way until they become fully susceptible
once more. With the assumption that acquired immunity lasts for 20 years,
50% of the infected population would be expected to be adults. In order
to achieve a result closer to the 2% actually observed it is necessary
to increase the duration of immunity as well as the number of intermediate
loops of lower immunity followed by boosts from infection. This was accomplished
by adding new compartments to the model in order to better simulate the
different levels of immunity occurring after disease. With the assumptions
of 50 years of acquired immunity and 10 intermediate loops of mild infection,
the model simulates results consistent with the pre-vaccination notification
data. The model also incorporates post-vaccine compart- ments and vaccine-related
waning immunity.
The overall conclusions were that the resurgence of pertussis
in the 1990s was largely due to a poorly protective vaccine, although
even with an effective vaccine there will be a shift to higher age groups
because of the intrinsic properties of the dynamics of pertussis, rather
than because of vaccine properties. Remaining with the current schedule
and vaccine will result in continued decreases in the number of cases.
Immunization of adolescents would lead to an overall reduction of 15%,
affecting primarily the age group 15-25 years rather than infants. Introduction
of adult immunization based on the current Td booster schedule would have
little impact.
Management of Pertussis
The Treatment of Pertussis: Old and
New Macrolides
Dr. Scott Halperin
Antibiotics eradicate B. pertussis from the nasopharynx
but have no effect on the clinical symptoms or course of pertussis unless
given in the early stages. They are therefore prescribed more for control
of transmission than for individual benefit. Erythromycin (preferably
estolate) 40-50 mg/kg daily for 10 days to a maximum of 1 g (for 14 days
to a maximum of 2 g in the U.S.) is the recommended macrolide in Canada,
and this should be started within 3 weeks after onset of cough. Cotrimoxazole
can be used if erythromycin is not tolerated.
The efficacy of erythromycin has been demonstrated(31).
However, it is not well tolerated, and adverse gastrointestinal effects
are reported more often after 14 than 7 days of treatment. In an RCT of
7 days versus 14 days of erythromycin estolate for children (and their
household contacts) with culture confirmed pertussis, it was found that
7 days of treatment were as effective as 14 days in terms of bacteriologic
cure (negative culture after treatment)(32). Adverse events
were less common with the 7-day course of treatment; however, there was
no difference in compliance rates between the two schedules.
Two newer macrolides, clarithromycin and azithromycin, have
been compared with erythromycin in two RCTs. In the first, culture positive
subjects (n = 62) were given either clarithromycin (15 mg/kg
daily) for 7 days or erythromycin estolate (40 mg/kg daily) for 14 days(33).
The two drugs were found to be equally effective, but clarithromycin was
better tolerated and resulted in higher compliance rates. In the second
study, comparing the same schedule of erythromycin estolate with 5 days
of azithromycin (10 mg/kg on the first day and then 5 mg/kg daily for
4 days) in 114 subjects, the results were similar, i.e. compliance with
azithromycin was better because of fewer adverse events, although it was
no more effective than erythromycin in treating pertussis (unpublished
data: Halperin S, Langley JM, Boucher F for PICNIC). The comparative cost
of the drugs - erythromycin being two to four times cheaper than
clarithromycin and azithromycin - may be a factor in the treatment
of choice.
Effectiveness of Prophylaxis
Dr. Gaston De Serres
Pertussis is spread by close contact with the respiratory
secretions of an infected person, and within households the secondary
attack rate tends to be higher in younger age groups. An RCT(34)
has shown a 67% efficacy of erythromycin prophylaxis in preventing culture
positive pertussis in household contacts, but its clinical impact was
very limited. Epidemiologic studies also suggest that chemo- prophylaxis
provides some benefit. However, it must be started as soon as possible
after the onset of cough in the primary case: the secondary attack rate
has been found to increase from 11% when prophylaxis was initiated within
21 days of cough onset to 29% if prophylaxis was delayed beyond 21 days(35).
When delayed by 21 days or more the secondary attack rate was similar
in those with and without prophylaxis.
There may be delay in the use of prophylaxis if the time
to diagnosis is long, either because the primary case did not consult
a physician straight away, the physician did not consider a diagnosis
of pertussis, or laboratory results were not available quickly. Deeks
et al. found that even in the presence of four symptoms of pertussis,
physicians diagnosed the disease in only 44% of cases(36).
Even after diagnosis, household contacts may not willingly undergo chemoprophylaxis
if the cost of a new macrolide is high (e.g. clarithromycin) or the drug
carries the risk of adverse events.
There is little evidence for the efficacy of prophylaxis
outside household and closed settings - for example, in the classroom.
However, household contacts should be targeted and possibly children in
home day care settings, particularly if there are very young infants present
in both cases.
Prophylaxis may prevent some cases, but it should be used
selectively because of the its limited positive impact.
Current Status and Problems with Outbreak Management:
Perspective from the Field
Ms. Karen Pielak
A survey of public health nurses and medical officers of
health has highlighted several areas of frustration that these health
professionals experience when following up pertussis cases and contacts.
Respondents were consistent in stating that 30 to 60 minutes was the time
required for each index case, and 15 to 30 minutes per close contact.
With an average of 10 to 12 contacts per case the process can take up
to 4 hours altogether. Getting in touch with contacts is very time-consuming,
and maintaining confidentiality (with regard to the name of the case)
can be difficult.
Other delays are those arising from laboratory investigation
- either because of constraints on resources or because general practitioners
do not consider pertussis in their differential diagnosis and do not order
the appropriate tests at an early stage - and case reporting. Delays
are likely to result in increased transmission, until contacts are given
chemoprophylaxis. The drugs used for chemoprophylaxis are a high cost
for some families, and many individuals are not willing to take antibiotics
when they have no symptoms, particularly if there are side effects. With
regard to immunization, it is difficult to ascertain the status in certain
children without an immunization registry in place. Updating the immunization
schedule for contacts of pertussis cases may be complicated by the fact
that there is only a combined acellular pertussis vaccine at present,
and extra doses of diphtheria and tetanus toxoid may not be warranted.
A further source of frustration is the lack of understanding on the part
of some community physicians that pertussis is a health concern for adults
as well as children, particularly as adults may be the ones most likely
to transmit the infection.
Suggestions for improved outbreak control include covering
the cost of chemoprophylaxis in order to increase compliance, using prescriptions
for antibiotics pre-signed by medical officers of health as a means of
expediting chemoprophylaxis, and reserving chemoprophylaxis for individuals
at greater risk of the complications of pertussis or those who are in
contact with unimmunized children or infants.
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