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Update on pertussis in children

Expert Rev. Anti Infect. Ther. 8(2), 163–173 (2010)

Ulrich Heininger
University Children’s Hospital
(UKBB), PO Box, CH-4005 Basel,
Switzerland
Tel.: +41 616 856 565
Fax: +41 616 856 012
ulrich.heininger@ukbb.ch
Pertussis (or whooping cough) is a frequent and important infectious disease of the respiratory
tract, mainly caused by the Gram-negative rod bacterium Bordetella pertussis. Although it
is frequently believed that pertussis is exclusively a ‘childhood disease’, in reality it occurs at
any age but is most serious in young infants. Adults are the main reservoir for B. pertussis
today and pertussis remains an endemic disease worldwide despite the availability of
comprehensive immunization programs that primarily target the pediatric population. There
are many reasons for these, and these include incomplete immunity following natural
infection as well as immunization and waning immunity over time. Manifestations of
B. pertussis infections vary by magnitude of the bacterial inoculum, age, immune status and
probably further yet unidentified individual factors. They can range from asymptomatic,
apnea and uncharacteristic cough to typical coughing spells with posttussive phlegm and/
or vomiting, and duration also varies between a few days and several months. Since
antibacterial treatment of pertussis is generally ineffective as it usually sets in too late, the
main focus should be on the prevention of pertussis by immunization. This apparently requires
more than immunization of children – that is, expanding routine immunization into
adolescence and adulthood.

Keywords : acellular • Bordetella pertussis • complication • disease • epidemiology • pertussis • prevention

• vaccine

“Scio nescio” (“I know that I don’t know”,
Sokrates, 469–399 BC).
Recently, several achievements have been made
in the area of pertussis with specific relevance for
the pediatric population. Importantly, new viru-
lence factors of the causative organism have been
identified, some of which are currently being
studied for their protective potential as vaccine
antigens [1] . Furthermore, several studies have
been performed to elucidate current transmission
patterns and contact sources for serious pertussis
disease in infants as well as the spectrum of clini-
cal presentations [2–6] . Finally, pertussis immu-
nization programs have recently been modified
in many industrialized countries by expanding
them to include adolescents and adults. This has
the potential to reduce the burden of pertussis in
children, provided that implementation of new
recommendations can be achieved [7,8] .
The goal of this review is to discuss these
advances and to provide a short overview of
the current knowledge on pertussis with a focus
on children as well as key references for the
interested reader.
Microbiology & virulence factors
The genus Bordetella currently includes seven
species that have been isolated from humans
including children. These are:
• Bordetella pertussis and Bordetella para­
pertussis, both long known to cause whooping
cough [9] ;
• Bordetella bronchiseptica, which is primarily a
pathogen in animals, also occasionally colo-
nizes the human respiratory tract and can
lead to less characteristic cough disease [10] ;
• Bordetella holmesii and Bordetella hinzii, isolated
from blood cultures during sepsis, most fre-
quently in patients with underlying chronic ill-
nesses [11,12] ; B. hinzii has also been isolated
from respiratory specimens in patients with
cystic fibrosis [13] ;
• Bordetella trematum, occasionally isolated
from wound and ear infections [14,15] ;
• Bordetella petrii, isolated from the environ-
ment, from patients with cystic fibrosis and
from a patient with mastoiditis [13,16] .

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 Review Heininger

This review, however, will focus on B. pertussis and B. parapertussis,
the causative organisms of pertussis.
Continuous advances are being made in basic pertussis research.
This has led to the identification of a number of new virulence
factors of B. pertussis and their secretion systems. Furthermore,
their putative roles during infection have been suggested based
on infection models in animals  [1] . Currently known virulence
factors and some of their characteristics are presented in Table 1.
Several of these antigen components are promising candidates for
a future generation of new pertussis vaccines.
Disease
Pertussis typically manifests as a cough illness. The clinical
spectrum is broad and ranges from mild respiratory symptoms
lasting a few days (‘atypical disease’) to a characteristic hacking
cough for several months (‘classic disease’). Although infection
with B. pertussis tends to be more severe on average compared
with B. parapertussis infection, the clinical overlap is substantial
and a firm etiological diagnosis can only be made by use of
microbiological tests [9] .
Classic pertussis advances through three clinical stages:
catarrhal (rhinorrhea with unspecific cough), paroxysmal (increas-
ing severity of cough, coughing spells, frequently followed by
whooping and emesis) and convalescent (decreasing frequency
and severity of cough). There is a broad range of complications
associated with B. pertussis infection. In children, these include
conjunctival hemorrhage, inguinal hernia, pneumonia, respira-
tory distress syndrome, seizures, encephalopathy, and – mainly
in young infants – apnea and sudden death [17] .
Numerous reports have described the frequency of signs and
symptoms associated with pertussis [18] . However, variability in
study settings, the populations under study and the diagnostic

Table 1. Major virulence factors of Bordetella pertussis.

Factor (gene) Bvg Molecule Major role Other functions Comments
regulation*
Pertussis toxin (ptx) Yes; + phase A protomer and Toxin and adhesion factor Causes leukocytosis Protective vaccine
multiple B subunits by lymphocytosis antigen
Filamentous Yes; + phase Large, filamentous Adhesion factor, Not known Need for inclusion in
hemagglutinin (fha) protein (220 kDa) predominantly in trachea; vaccine questionable
implicated in immune
modulation
Fimbriae 2 and 3 Yes; + phase Small, filamentous Adhesion factor; Agglutinogens; Important stimulator of
(fim2, fim3, fimX) proteins (~23 kDa) predominantly in trachea sustain infection host’s immune response
(interaction with
phagocytes)
Pertactin (prn) Yes; + phase 69-kDa outer Adhesion factor Major protective Protective vaccine
membrane protein antigen (mouse antigen
model)
Adenylate cyclase Yes; + phase Protein toxin Toxin; inhibits phagocytosis Inhibits chemotaxis Promising candidate for
(cya) by increase of cAMP and induces future vaccines
apoptosis of
macrophages
Tracheal cytotoxin No Peptidoglycan Toxin; paralyses mucociliary Inhibits DNA Nonimmunogenic, so
(tct) derivative clearance system synthesis and cell not suitable for vaccine
death
Dermonecrotic toxin Yes; + phase Heat-labile toxin Toxin; dermal necrosis Effect only after Role in human
(dnt) (140 kDa) and vasoconstriction injection in skin disease unknown
Tracheal colonization Yes; + phase Proline-rich protein Adhesion factor; Autotransporter C-terminal homology to
factor (tcfA) predominantly in trachea Prn, Brk and Vag-8
Bordetella resistance Yes; + phase Outer membrane Adhesion factor Provides resistance to C-terminal homology to
to killing factor (brk) protein (32 kDa) complement Prn, Tcf and Vag-8
Virulence-activated Yes; + phase Outer membrane Adhesion factor Autotransporter C-terminal homology to
gene 8 (vag-8) protein (95 kDa) Prn, Tcf and Brk
Type III secretion Yes; + phase Apparatus, consists Secrets effector proteins Immunomodulatory Ongoing intensive
system (bscN) of 22 components into host cells role suggested research
BteA (bteA) Yes; + phase Linked to type III Induction of cytotoxicity Persistent infection Potential vaccine antigen
secretion (72 kDa) (animal model)
*
A single genetic locus (Bvg= Bordetella virulence gene) that regulates the expression of several B. pertussis-related virulence factors.

164 Expert Rev. Anti Infect. Ther. 8(2), (2010)


tests applied make meaningful comparisons impossible. In general,
with progress made in the field of pertussis diagnosis, it has become
more and more evident that atypical mild illness is much more
common than previously known  [19] . This is particularly true in
the case of partially immune individuals (either vaccinated or with
previous episodes of pertussis), but also in nonimmune patients
with primary infection [19–22] . One study by our group comprised
1860 children and adolescents with culture-positive pertussis and
a standardized clinical follow-up. Overall, 38% of patients had
cough illness duration of less than 4 weeks, 18% had cough without
paroxysms, 21% had cough without whooping and 47% had cough
without posttussive vomiting [19] . In studies, in which PCR was
used for diagnosis of B. pertussis infection, the frequency of mild
cases compared with typical presentations was even higher [20,23] .
It has long been known that clinical manifestations of pertus-
sis vary with age [24] . Pertussis is most severe in young infants
with a case–fatality rate of approximately 1% and frequent other
complications such as encephalopathy (i.e., apnea and seizures)
and respiratory failure [25–27] . Importantly, B. pertussis infection
has also been identified in association with sudden infant death
by case observations and epidemiological studies [28–30] .
Diagnosis
A clinical diagnosis can only be made if disease presents with typical
symptoms. However, even then a distinction between B. pertussis
and B. parapertussis infection is impossible without microbiologi-
cal confirmation and infection by several other microorganisms,
including adenovirus, parainfluenza virus, respiratory syncytial
virus, Mycoplasma pneumoniae and Chlamydia pneumoniae, can
mimic the clinical symptoms of pertussis [31,32] . Therefore, appro-
priate microbiological tests should be applied if a firm diagnosis of
pertussis is to be made.
Even more problematic is the situation in patients with un­specific
cough illness. It is a matter of ongoing debate and a question of
financial resources whether an etiological diagnosis should be estab-
lished in an individual patient. Given the fact that pertussis is a vac-
cine-preventable disease (and therefore is of epidemiologic interest),
which frequently presents with atypical symptoms and still is highly
transmissible (and therefore isolation measurements are advisable),
and for which antibiotic treatment is available (and therefore of
potential benefit in exposed individuals), it is the author’s strong
conviction that a microbiological diagnosis should be attempted
whenever possible. In outbreak and high-risk situations, such as
when vulnerable individuals like young infants are exposed or
otherwise involved, the author believes that this is even mandatory.
Formerly, isolation of the organism from nasopharyngeal speci-
mens used to be the diagnostic ‘gold standard’. However, sensitivity
of culture is poor, especially:
• In immunized patients where the bacterial load is usually low
• After onset of antibiotic treatment
• If the course of illness has progressed for more than 3 weeks [25,33]
Even so, isolation of the organism by culture is advisable as it allows
for antibiotic susceptibility monitoring and typing studies [34,35] .
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Update on pertussis in children Review
Today, PCR-based methods have largely replaced culture as
the preferred diagnostic tool to identify Bordetella species from
respiratory secretions in early stages of the disease [36] . Various
different procedures to identify B. pertussis and B. parapertussis
DNA in respiratory tract specimens have been developed and
introduced in daily clinical practice, at least in many developed
countries. Higher sensitivity and timely reporting of results are
the major advantages compared with conventional culture [20,37] .
It should be noted that strict adherence to standardized pro-
tocols and quality assurance are necessary to avoid laboratory
contamination, which can lead to false-positive results [38,39] .
In advanced pertussis disease (duration of cough for 3 weeks or
longer), demonstration of the presence of the organism becomes
increasingly difficult and standardized serologic assays are then
the most sensitive diagnostic method [18,31] . However, several
issues hamper widespread use of serology to diagnose pertussis.
These include the lack of standardized test assays, high costs and
the need to demonstrate changes of antibody values in paired
serum samples (from acute and convalescent phase). Obtaining
a single specimen is more practical for routine purposes, but age-
matched control groups taking the immunization status into
account are required to establish meaningful cut-off values [40,41] .
This is explained by the fact that in immunized individuals, the
presence of B. pertussis-specific antibodies may be due to pre-
vious immunization, exposure to the wild-type organism, or a
mixture of both. In unvaccinated children, sensitivity of serology
reached 89% when a combination of IgG antipertussis toxin and
IgG or IgA antifilamentous hemag­glutinin was used and when
serum specimens were taken late (5–10 weeks after the onset of
symptoms) during the disease [42] .
In conclusion, PCR should be applied in the early and mid phase
of suspected pertussis disease (up to 3 weeks) whereas the strength
of serology is evident in late phases and in retrospective as well
as for the assessment of seroprevalence in epidemiologic studies.
Treatment
Treatment of pertussis should be both symptomatic and
directed at the causative organism – that is, with antibiotics.
Unfortunately, the armentarium and effectiveness of symptomatic
treatment are quite limited [17] . Symptomatic treatment aims at
avoiding coughing and support of liquids and nutrition. In severe
disease, hospitalization is required. Monitoring of oxygen satura-
tion in the blood may then be required and supplemental oxygen
is frequently necessary, sometimes in the intensive care unit with
assisted ventilation, especially in infants with apnea, pneumonia
and respiratory distress. Treatment is most challenging in young
infants with extreme leukocytosis (>100,000/µl) and pulmonary
hypertension, frequently leading to respiratory and cardiovascu-
lar failure, which can be fatal despite maximal treatment efforts
including pulmonary artery vasodilators and extracorporeal mem-
brane oxygenation [26,43,44] . Autopsy findings have shown small
and medium-sized pulmonary arteries filled with lymphocytes
and neutrophils, but not pulmonary thrombosis [44] . Successful
exchange transfusions to lower the peripheral leukocyte load have
been described in this context [43] .
165
 Review Heininger
There are also anecdotal reports on the use of corticosteroids
to relieve symptoms of pertussis. In one such study, 7 days of
steroids (plus erythromycin) reduced duration of cough and the
number of paroxysms as well as the number of vomiting episodes
[45] . Unfortunately, however, the study was not controlled and no
further trials have since been performed. Therefore, use of ste-
roids can not be recommended generally but remains an experi-
mental treatment based on an individual decision. Similarly, the
use of salbutamol has been proposed to be beneficial based on
case observations, but no randomized controlled trials have been
performed to support this treatment modality [46] .
By contrast, antibiotic treatment of B. pertussis and B. par­
apertussis infections has been validated and is generally rec-
ommended  [17] . Macrolides are the first-choice drugs, as they
demonstrate almost universal susceptibility with very few excep-
tions [47,48] . Erythromycin, clarithromycin and azithromycin have
been tested in vitro and in various clinical settings, including
prospective, randomized, controlled trials [47,49–51] . In general,
better tolerability and equal, if not better, efficacy of modern
macrolides (azithromycin and clarithromycin) led many experts
to prefer these antibiotics to erythromycin. The main benefit of
antibiotic treatment in patients with pertussis is the rapid elimi-
nation of the organism from the nasopharynx, thereby reducing
trans­mission to exposed contact individuals [52] . By contrast, the
effect of antibiotic treatment on reducing symptoms of the patient
is limited (if started within 2 weeks of onset of symptoms) or lack-
ing, especially when treatment is started late during the disease
– that is, beyond 2 or 3 weeks after the onset of symptoms. The
optimal duration of antibiotic treatment is a matter of ongoing
debate. Early observations that showed treatment failures with
7-day treatment led to the recommendation to treat for 2 weeks,
although no controlled studies had validated this procedure [53] .
However, the fact that bacterial eradication was shown to occur
within a few days after the onset of treatment again challenged
the 2-week treatment recommendation. In a highly vaccinated
pediatric population in Canada, efficacy of 7 days of erythromy-
cin estolate was not inferior to the conventional 14 days and this
has led many countries to recommend short-course treatment
with erythromycin today [54] . Similarly, 7 days of clarithromycin
and 5 days of azithromycin have been tested successfully in one
small study in Japan, with complete bacterial eradication at the
end of treatment [55] .
Macrolides are usually well tolerated. Of specific note, pyloric
stenosis has been observed in association with erythromycin and
azithromycin during treatment of pertussis in young infants [56–58] .
In patients with macrolide allergy or in young infants, cotrimoxazole
(trimethorpime-sulfa) is a valid alternative [59] .
The role of antibiotic prophylaxis in individuals exposed to
patients with pertussis is an issue of controversial discussion. The
main argument for generally recommending prophylaxis is to
avoid spread of the organism and to protect vulnerable patients,
such as young infants. Most experts agree that vulnerable exposed
patients should receive prophylaxis as soon as possible, regard-
less of their pertussis immunization status [60] . One could also
argue that antibiotic prophylaxis should be recommended to any
166
exposed individual, even if fully vaccinated, as the efficacy of
pertussis vaccines is suboptimal (see later). However, in many
societies, this is been seen as an unjustified overuse of antibiotics.
In the author’s view, antibiotic prophylaxis should not be gener-
ally recommended but should be based on individual counseling.
In any case, if prophylaxis is initiated early after exposure, its
effectiveness is convincing [61–63] .
Epidemiology
Characterizing the epidemiology of pertussis is extremely difficult.
Major problems in this context are the following:
• Lack of a uniform case definition
• Lack of reliable and widely available diagnostic tests
• Underconsulting, under-recognition, underdiagnosis and
under-reporting
• Lack of uniform, comparable surveillance systems
This is the reason why reported incidence rates of pertussis in
Europe may vary from less than one to over 180 per 100,000 inhab-
itants per year [64] . In reality, incidence rates in all countries are
probably very similar and may reach 500 per 100,000, as has been
demonstrated in a prospective vaccine efficacy trial in adults in the
USA [65] . These figures relate to symptomatic pertussis disease (with
cough), whereas oligosymptomatic (catarrhal symptoms and mild
cough) or asymptomatic B. pertussis infections are probably even sig-
nificantly higher but may contribute to widespread transmission of
the organism in highly vaccinated populations [66] . B. parapertussis
infections comprise a small proportion of clinical pertussis disease,
although this may vary between 0 and up to 30% for short periods
of time, depending on local and timely limited outbreaks [17] .
It is clear that humans are the only natural host for B. pertussis
and transmission occurs by droplets from the respiratory tract of
an infected person to nonimmune contact individuals. Pertussis is
highly transmissible with an estimated R0 (basic reproduction rate,
i.e., the number of secondary cases induced by one primary case) of
15–17 [67] . Therefore, it is no surprise that pertussis has remained
endemic in virtually every country worldwide, despite high immu-
nization coverage in children in many populations [68] . Increasing
uptake of pertussis vaccines in national immunization programs
has led to a steady decrease in the proportion as well as absolute
numbers of pertussis cases in children beyond infancy during the
last few decades in many parts of the world [69–73] . This is an effect
of direct protection. However, pertussis still occurs frequently in
infants under 3 months of age – those who are too young to be
protected by immunization. Moreover, because vaccine-induced
immunity wanes over time and also the chance for ‘natural boost-
ers’ has probably decreased, the observed parallel increase of cases
in adolescents and adults is not unexpected but well explained.
Still, some doubts remain as to whether the observed epidemio-
logical age shift is real or whether it is a consequence of increased
awareness and better diagnostic tools [74] .
A further interesting observation is the fact that not only sib-
lings but also adults in the families are frequently the source
of B. pertussis infection in young, unimmunized and therefore
Expert Rev. Anti Infect. Ther. 8(2), (2010)

unprotected infants. Although this is now an area of intensive
research, the role of adults in the transmission of pertussis has
long been known and is only being rediscovered today  [75–77] .
Recent studies investigating household transmissions of B. per­
tussis infection to infants are summarized in Table 2 . Parents were
the most frequent source of infection, with values ranging from
18 to 22% overall and 44 to 60% in cases where at least one
source was identified.
Immunization
Pertussis, caused by B. pertussis, can be prevented by active immu-
nization. No specific vaccines against B. parapertussis are available.
Yet clinical cross-protection has been demonstrated for one acel-
lular pertussis vaccine [78] . In this randomized, controlled, double-
blind study, efficacy against B. parapertussis infection was 50%
for the diphtheria–tetanus–acellular pertussis (DTaP) vaccine
(95% CI: 5–74%) and 21% for the diphtheria–tetanus–pertussis
(DTP) vaccine (95% CI: -45–56%; i.e., not significant).
However, compared with other standard childhood immuni-
zations, vaccine efficacy with formerly used whole-cell pertussis
vaccines (DTP) and the more recently introduced acellular
component vaccines (DTaP ) is less than optimal and has only
been studied formally for the first three or four doses [17,79–85] .
Little is known about the clinical efficacy of further booster
doses, but immunogenicity studies are very favorable, sug-
gesting that efficient priming takes place during the initial
immuni­z ation series in infancy and persists into adolescence
and adulthood [86–88] . Concerns about the side effects of whole-
cell pertussis vaccines, although unsubstantiated, prompted the
development of acellular component pertussis vaccines in the
late 1980s and early 1990s [89] . These vaccines contain detoxi-
fied pertussis toxin and up to four further antigens and are
Table 2. Epidemiological studies on household members as the source of pertussis transmission to infants.
Country of origin Study population
UK 25 infants younger than 5 months of age admitted
to ICU because of proven pertussis
USA 616 infants with proven pertussis
France 1668 hospitalized infants under 6 months of age
with proven pertussis
Multinational 99 infants admitted to ICU because of
proven pertussis
Multinational 95 infants under 6 months of age admitted to
hospital because of proven pertussis
*
Only n for household contacts are presented; remaining sources were nonhousehold contacts.
ICU: Intensive care unit.
www.expert-reviews.com
Update on pertussis in children Review
less reactogenic than formerly used whole-cell vaccines [17] .
Consequently, most countries in Europe and developed coun-
tries elsewhere today exclusively use acellular pertussis vaccines.
Unfortunately, however, vaccination coverage is suboptimal in
many places, especially with booster doses [90] . Current pertussis
vaccination schedules in Europe are summarized in Table 3. As
can be seen, most countries recommend four to five doses in the
first few years of life. The primary schedule either consists of
three doses with short intervals between doses (mainly at 2–3–4
or 2–4–6 months of age), followed by a first booster (fourth
dose) in the second year of life. Some Scandinavian and other
European countries prefer a prolonged interval between the
second and third dose (3–5–11 or –12 month schedule), which
makes the ‘booster dose’ in the second year of life superflu-
ous, thus saving one dose. This also has disadvantages. Recent
epidemiological observations in Finland raise doubts about
the efficiency of this schedule as it leaves many young infants
unprotected for a prolonged period of time [91] . Starting the
immunization series at 2 months at the latest therefore seems
prudent, especially since it has been demon­strated that the first
dose of pertussis vaccine can prevent serious disease with an
efficacy of approximately 70% [92] . However, at least three doses
are necessary for complete protection [92,93] . Since pertussis is
most serious in young infants, attempts have been made to start
the immunization series against pertussis earlier with one extra
dose in newborns [94,95] . In principle, this is possible with acel-
lular vaccines which, in contrast to whole-cell vaccines, have
been shown to not interfere immunologically with persisting
maternal antibodies [96] . In one study in the USA, 50 infants
2–14 days of age received either a combined DTaP and hepatitis
B vaccine or hepatitis B vaccine alone (control). At 2, 4, 6 and
17 months of age, four further doses of DTaP (and other routine
Outcome* Ref.
Primary case: [2]
Parent: n = 11 (44%)
Sibling: n = 6 (24%)
Source discovered in 264 cases: [3]
Parent: n = 123 (47%; 20% of total)
Grandparent: n = 22 (8%; 4% of total)
Sibling: n = 52 (20%; 8% of total)
Source discovered in 892 cases: [4]
Parent: n = 491 (55%; 29% of total)
Sibling: n = 223 (25%; 13% of total)
>1 source (n = 30) discovered in 24 cases: [5]
Parent: n = 18 (60%; 18% of total)
Other adult: n = 6 (20%; 6% of total)
Sibling: n = 5 (17%; 5% of total)
>1 source discovered in 44 cases: [6]
Parent: n = 27 (55%; approx 25% of total)
Grandparent: n = 3 (6%; approx. 3% of total)
Sibling: n = 8 (16%; approx. 5% of total)
167
 Review Heininger

Table 3. Pertussis immunization recommendations in Europe*.

Country No. of doses Type of vaccine Schedule (recommended minimal age) Comments
Albania 4 WCPV 2–4–6 months/2 years

Austria >6 APV 2–3–4 months/12 months/12–13 years/>18 years Every 10 years in

adults
Belgium 6 APV 2–3–4 months/13 months/5–7 years/14–16 years

Bosnia/Herzegowina 4 APV/WCPV 2–4–6 months/5 years APV for doses 1–3

Croatia 5 APV 2–4–6 months/18 months/3 years

Cyprus 5 APV 2–4–6 months/15–18 months/4–6 years

Czech Republic 5 APV/WCPV 3–4–5 months/18 months/5 years APV for doses 1–4

Denmark 4 APV 3–5–12 months/5 years

Estonia 5 APV 3–4–6 months/2 years/6–7 years

Finland 4 APV 3–5–12 months/6 years

Former Yugoslav 5 WCPV 4–6–8 months/18 months/4 years

Republic of
Macedonia
France 6 APV 2–3–4 months/16 months/11–13 years/26–28 years
Germany 7 APV 2–3–4 months/11–14 months/ 5–6 years/
9–17 years/>18 years
Greece 6 WCPV/APV 2–4–6 months/15–18 months/4–6 years/11–12 years WCPV for doses 1–4

Hungary 5 APV 2–3–4 months/18 months/6 years

Iceland 5 APV 3–5–12 months/5 years/14 years

Ireland 4 APV 2–4–6 months/4–5 years

Italy 4 APV 3–5–11 months/5–6 years

Latvia 4 APV 3–4–6 months/18 months

Lithuania 5 APV 2–4–6 months/18 months/6 years

Luxemburg >6 APV 2–3–11 months/5–6 years/15–16 years Every 10 years

in adults
Malta 3 APV 2–3–4 months

Montenegro 4 WCPV 2–4–6 months/18 months

The Netherlands 5 APV 2–3–4 months/11 months/4 years

Norway 4 APV 3–5–12 months/7 years

Poland 4 WCPV/APV 2–3–5 months/16–18 months/6 years WCPV for doses 1–4

Portugal 5 APV 2–4–6 months/18 months/5–6 years

Romania 5 APV/WCPV 2–4–6 months/12 months/30–35 months APV for doses 1–4

Russian Federation 4 WCPV 3–4–6 months/18 months

San Marino 4 APV 2–5–11 months/5–6 years

Serbia 4 WCPV 2–3–5 months/18 months

Based on information obtained from the WHO [101].
*

APV: Acellular pertussis vaccine; WCPV: Whole-cell pertussis vaccine.

168 Expert Rev. Anti Infect. Ther. 8(2), (2010)

 Update on pertussis in children Review

Table 3. Pertussis immunization recommendations in Europe* (cont.).

Country No. of doses Type of vaccine Schedule (recommended minimal age) Comments
Slovakia 5 APV 2–4–10 months/2 years/5 years

Slovenia 4 APV 3–4–6 months/18 months

Spain 5 APV 2–4–6 months/15–17 months/4–6 years

Sweden 5 APV 3–5–12 months/5–6 years/10 years

Switzerland 5 APV 2–4–6 months/15–24 months/4–7 years

Turkey 4 APV 2–4–6 months/18 months 

UK/Northern Ireland 4 APV 2–3–4 months/3–5 years

Based on information obtained from the WHO [101].
*

APV: Acellular pertussis vaccine; WCPV: Whole-cell pertussis vaccine.

vaccines) were administered. Although all vaccines were well against pertussis may provide protection much earlier than the
tolerated, unfortunately infants with a neonatal pertussis vac- conventional initiation of the immunization series at 2 months
cine dose had significantly lower geometric mean antibody val- of age. Unfortunately, however, the monovalent acellular
ues for several pertussis antigens after immunization compared pertussis vaccine in this study was experimental and is not
with controls [94] . generally available.
By contrast, in a different randomized controlled trial in Other considerations to protect young infants from pertussis
Germany, 121 neonates received either monovalent acellular are maternal immunization during pregnancy and the so-called
pertussis vaccine or hepatitis B vaccine at birth, followed by cocoon strategy [97] . The major hurdle with maternal immuniza-
vaccination with the hexavalent DTaP–hepatitis B virus–inac- tion in pregnancy is safety concern. Despite the fact that pertus-
tivated polio virus/Haemophilus influenzae type b combina- sis component vaccines are all inactivated, coinciding adverse
tion vaccine at 2, 4 and 6 months used on a routine basis in events in the unborn child or newborn that could be attributed to
Germany [95] . Tolerability of vaccinations did not differ between the vaccine make studies in this area problematic. Alternatively,
groups. Serological assays at 3 months of age revealed that vac- attempts have been made to provide indirect protection to new-
cination with an extra dose of acellular pertussis vaccine at borns by immunizing close contacts, mainly household mem-
birth had induced significantly higher antibody responses to bers, shortly before or after birth of the child (‘cocoon strategy’).
the three pertussis antigens contained in the vaccine compared This could reduce the risk of acquisition of B. pertussis infection
with controls. Furthermore, at 7 months of age, serum antibody of the newborn or young infant by increasing the likelihood
concentrations against pertussis antigens were similar in both of protection in contact individuals [98] . Unfortunately, how-
groups, and all subjects had reached what the authors consid- ever, this strategy is difficult to implement as it requires high
ered to be sero­protective concentrations against diphtheria, compliance in obstetric units and intensive educational efforts.
tetanus and poliovirus types 1, 2 and 3. However, concentra- Therefore, in the author’s view, newborn immunization appears
tions of antibodies against H. influenzae type b and hepatitis to be the most promising strategy to protect young infants.
B virus were significantly lower in the acellular pertussis vac- In conclusion, progress has been made in the field of pertussis
cine birth group, although the differences were not considered research over the last two decades. However, several important
to be clinically significant. Therefore, neonatal immunization issues remain. These include improved availability of laboratory
Key issues
• Pertussis (whooping cough) is a common respiratory tract infection, mainly caused by Bordetella pertussis and less frequently by
Bordetella parapertussis.
• Pertussis is not an exclusive ‘childhood disease’ but occurs at any age, worldwide, endemically. It is, however, most severe in infants,
with complications such as pneumonia, respiratory distress syndrome, seizures, encephalopathy, apnea and sudden death.
• A large number of virulence factors of B. pertussis are known but their precise role in the pathogenesis of pertussis is not
completely understood.
• A firm diagnosis can only be made by use of specific microbiological tests, such as PCR, culture and serology.
• Pertussis is vaccine-preventable, although vaccine efficacy is suboptimal, ranging from 50 to 85%, depending on the clinical outcome.
• Symptomatic treatment of pertussis is of limited value whereas causative treatment with antibiotics (mainly macrolides) is relatively
efficient in eradicating the organisms form the respiratory tract.
• Neonatal immunization against pertussis is a promising new strategy to provide protection much earlier than the conventional initiation
of the immunization series at 2 months of age.

www.expert-reviews.com 169
 Review Heininger

methods for the diagnosis of pertussis, increasing the coverage • Better define the epidemiology of pertussis disease including
of all recommended pertussis immunizations and, most impor- target groups for intensified protective measurements
tantly, identification of the best strategy to avoid serious pertussis
• Better define its clinical characteristics
in young infants.
• Monitor longitudinal changes
Expert commentary
Ultimately, it should be possible to eliminate pertussis disease,
Several issues regarding pertussis remain to be solved: improvement
although currently this seems to be very optimistic.
and harmonization of disease surveillance, wider availability and
standardization of diagnostic tests, increasing immunization cover-
age as well as protection of the young, unimmunized infant. The fact Financial & competing interests disclosure
that pertussis has not been eliminated anywhere can be explained by The author has been a member of the Global Pertussis Initiative and C.O.P.E
incomplete vaccination coverage, suboptimal vaccine efficacy, lim- (Consensus on Pertussis Booster Immunization in Europe), scientifically
ited duration of protection after natural disease and immunization, independent expert groups with financial support by Sanofi Pasteur MSD
and a lack of regular booster doses beyond childhood. and GlaxoSmithKline. The author has received speaker’s honoraria for
product-independent presentations at scientific and educational conferences
Five-year view related to several immunization topics, including pertussis vaccines from
Global harmonization of case definitions for pertussis should be several pharmaceuticl companies including manufacturers of pertussis vac­
feasible within the near future. Based on this, surveillance sys- cines. The author has no other relevant affiliations or financial involvement
tems for pertussis should be harmonized internationally. To avoid with any organization or entity with a financial interest in or financial
logistic burden and unrealistic costs, countries should consider conflict with the subject matter or materials discussed in the manuscript apart
establishing sentinel systems in ambulatory and hospital settings, from those disclosed.
supported by powerful diagnostic tools, such as PCR. Such systems No writing assistance was utilized in the production of this
will allow us to: manuscript.
8 Forsyth KD, Wirsing von Konig CH, 13 Spilker T, Liwienski AA, LiPuma JJ.
References Tan T, Caro J, Plotkin S. Prevention of Identification of Bordetella spp. in
Papers of special note have been highlighted as: pertussis: recommendations derived from respiratory specimens from individuals
• of interest the second Global Pertussis Initiative with cystic fibrosis. Clin. Microbiol.
•• of considerable interest roundtable meeting. Vaccine 25, Infect. 14, 504–506 (2008).
1 Shrivastava R, Miller JF. Virulence factor 2634–2642 (2007). 14 Daxboeck F, Goerzer E, Apfalter P,
secretion and translocation by Bordetella 9 Heininger U, Stehr K, Schmitt-Grohé S Nehr M, Krause R. Isolation of Bordetella
species. Curr. Opin. Microbiol. 12, 88–93 et al. Clinical characteristics of illness trematum from a diabetic leg ulcer.
(2009). caused by Bordetella parapertussis Diabet. Med. 21, 1247–1248 (2004).
2 Crowcroft NS, Booy R, Harrison T et al. compared with illness caused by 15 Vandamme P, Heyndrickx M,
Severe and unrecognised: pertussis in UK Bordetella pertussis. Pediatr. Infect. Dis. J. Vancanneyt M et al. Bordetella trematum
infants. Arch. Dis. Child. 88, 802–806 13, 306–309 (1994). sp. nov., isolated from wounds and ear
(2003). infections in humans, and reassessment of
• Classical publication that elucidates the
3 Bisgard KM, Pascual FB, Ehresmann KR clinical spectrum of pertussis caused by Alcaligenes denitrificans Rüger and Tan
et al. Infant pertussis: who was the source? Bordetella parapertussis in comparison 1983. Int. J. System. Bacteriol. 46,
Pediatr. Infect. Dis. J. 23, 985–989 with that caused by Bordetella pertussis. 849–858 (1996).
(2004). 16 Stark D, Riley LA, Harkness J, Marriott
10 Stefanelli P, Mastrantonio P, Hausman
4 Bonmarin I, Levy-Bruhl D, Baron S et al. SZ, Giuliano M, Burns DL. Molecular D. Bordetella petrii from a clinical sample
Pertussis surveillance in French hospitals: characterization of two Bordetella in Australia: isolation and molecular
results from a 10 year period. Euro. bronchiseptica strains isolated from identification. J. Med. Microbiol. 56,
Surveill. 12, 1–8 (2007). children with coughs. J. Clin. Microbiol. 435–437 (2007).
5 Kowalzik F, Barbosa AP, Fernandes VR 35, 1550–1555 (1997). 17 Cherry JD, Heininger U. Pertussis and
et al. Prospective multinational study of 11 Mazengia E, Silva EA, Peppe JA, Timperi other Bordetella infections. In: Textbook of
pertussis infection in hospitalized infants R, George H. Recovery of Bordetella Pediatric Infectious Diseases (6th Edition).
and their household contacts. Pediatr. holmesii from patients with pertussis-like Feigin RD, Cherry JD, Demmler-
Infect. Dis. J. 26, 238–242 (2007). symptoms: use of pulsed-field gel Harrison GJ, Kaplan SL (Eds). WB
6 Wendelboe AM, Njamkepo E, Bourillon electrophoresis to characterize circulating Saunders, PA, USA, 1683–1706 (2009).
A et al. Transmission of Bordetella pertussis strains. J. Clin. Microbiol. 38, 2330–2333 18 Mattoo S, Cherry JD. Molecular
to young infants. Pediatr. Infect. Dis. J. (2000). pathogenesis, epidemiology, and clinical
26, 293–299 (2007). 12 Weyant RS, Hollis DG, Weaver RE et al. manifestations of respiratory infections
7 Robert Koch-Institut: Impfempfehlungen Bordetella holmesii sp. nov., a new due to Bordetella pertussis and other
der Ständigen Impfkommission am Gram-negative species associated with Bordetella subspecies. Clin. Microbiol.
Robert Koch-Institut/Stand Juli 2009. septicemia. J. Clin. Microbiol. 33, 1–7 Rev. 18, 326–382 (2005).
Epidemiol. Bull. 30, 279–298 (2009). (1995).

170 Expert Rev. Anti Infect. Ther. 8(2), (2010)


•• Utmost source of information on all
aspects of pertussis.
19 Heininger U, Cherry JD, Eckhardt T,
Lorenz C, Christenson P, Stehr K. Clinical
and laboratory diagnosis of pertussis in the
regions of a large vaccine efficacy trial in
Germany. Pediatr. Infect. Dis. J. 12,
504–509 (1993).
20 Waters V, Jamieson F, Richardson SE,
Finkelstein M, Wormsbecker A,
Halperin SA. Outbreak of atypical
pertussis detected by polymerase chain
reaction in immunized preschool-aged
children. Pediatr. Infect. Dis. J. 28,
582–587 (2009).
21 Narkeviciute I, Kavaliunaite E,
Bernatoniene G, Eidukevicius R.
Clinical presentation of pertussis in fully
immunized children in Lithuania. BMC
Infect. Dis. 5, 40 (2005).
22 Long S, Lischner H, Deforest A, Clark J.
Serologic evidence of subclinical pertussis
in immunized children. Pediatr. Infect.
Dis. J. 9, 700–705 (1990).
23 Edelman K, Nikkari S, Ruuskanen O,
He Q, Viljanen M, Mertsola J. Detection
of Bordetella pertussis by polymerase chain
reaction and culture in the nasopharynx of
erythromycin-treated infants with
pertussis. Pediatr. Infect. Dis. J. 15, 54–57
(1996).
24 Cherry JD, Brunell PA, Golden GS,
Karzon DT. Report of the task force on
pertussis and pertussis immunization –
1988. Pediatrics. 81(Suppl.), 939–984
(1988).
25 Heininger U, Klich K, Stehr K, Cherry JD.
Clinical findings in Bordetella pertussis
infections: results of a prospective
multicenter surveillance study. Pediatrics
100(6), E10 (1997).
26 Halasa NB, Barr FE, Johnson JE,
Edwards KM. Fatal pulmonary
hypertension associated with pertussis in
infants: does extracorporal membrane
oxygenation have a role? Pediatrics 112,
1274–1278 (2003).
27 Surridge J, Segedin ER, Grant CC.
Pertussis requiring intensive care. Arch. Dis.
Child. 92, 970–975 (2007).
28 Heininger U, Stehr K, Schmidt-Schläpfer G
et al. Bordetella pertussis infections and
sudden unexpected deaths in children. Eur.
J. Pediatr. 155, 551–553 (1996).
29 Lindgren C, Milerad J, Lagercrantz H.
Sudden infant death and prevalence of
whooping cough in the Swedish and
Norwegian communities. Eur. J. Pediatr.
156, 405–409 (1997).
www.expert-reviews.com
Update on pertussis in children
30 Crowcroft NS, Andrews N, Rooney C,
Brisson M, Miller E. Deaths from pertussis
are underestimated in England. Arch. Dis.
Child. 86, 336–338 (2002).
31 Wood N, McIntyre P. Pertussis: review of
epidemiology, diagnosis, management and
prevention. Paediatr. Respir. Rev. 9,
201–211 (2008).
32 Wirsing von König CH, Rott H,
Bogaerts H, Schmitt HJ. A serologic study
of organisms possibly associated with
pertussis-like coughing. Pediatr. Infect.
Dis. J. 17, 645–649 (1998).
33 Edelman K, Nikkari S, Ruuskanen O,
He Q, Viljanen M, Mertsola J. Detection of
Bordetella pertussis by polymerase chain
reaction and culture in the nasopharynx of
erythromycin-treated infants with pertussis.
Pediatr. Infect. Dis. J. 15, 54–57 (1996).
34 Heininger U, Frei R, Cherry JD, Stehr K.
Comparison of pulsed field gel
electrophoresis patterns of Bordetella
pertussis isolates from unvaccinated
children with severe or mild pertussis.
Pediatr. Infect. Dis. J. 23, 211–217 (2004).
35 Bartkus JM, Juni BA, Ehresmann K et al.
Identification of a mutation associated with
erythromycin resistance in Bordetella
pertussis: implications for surveillance of
antimicrobial resistance. J. Clin. Microbiol.
41, 1167–1172 (2003).
36 Fry NK, Duncan J, Wagner K et al. Role of
PCR in the diagnosis of pertussis infection
in infants: 5 years’ experience of provision
of a same-day real-time PCR service in
England and Wales from 2002 to 2007.
J. Med. Microbiol. 58, 1023–1029 (2009).
37 Heininger U, Schmidt-Schläpfer G,
Cherry JD, Stehr K. Clinical validation of a
polymerase chain reaction assay for the
diagnosis of pertussis by comparison with
serology, culture, and symptoms during a
large pertussis vaccine efficacy trial.
Pediatrics 105(3), E31 (2000).
38 Cherry JD, Grimprel E, Guiso N,
Heininger U, Mertsola J. Defining
pertussis epidemiology: clinical,
microbiologic and serologic perspectives.
Pediatr. Infect. Dis. J. 24, S25–S34 (2005).
39 Meade BD, Bollen A. Recommendations for
use of the polymerase chain reaction in the
diagnosis of Bordetella pertussis infections.
J. Med. Microbiol. 41, 51–55 (1994).
40 Baughman AL, Bisgard KM, Edwards KM
et al. Establishment of diagnostic cutoff
points for levels of serum antibodies to
pertussis toxin, filamentous hemagglutinin,
and fimbriae in adolescents and adults in
the United States. Clin. Diagn. Lab.
Immunol. 11, 1045–1053 (2004).
Review
41 Bonhoeffer J, Bar G, Riffelmann M,
Soler M, Heininger U. The role of
Bordetella infections in patients with acute
exacerbation of chronic bronchitis. Infection
33, 13–7 (2005).
42 Wirsing von König CH, Gounis D,
Laukamp S, Bogaerts H, Schmitt HJ.
Evaluation of a single-sample serological
technique for diagnosing pertussis in
unvaccinated children. Eur. J. Clin.
Microbiol. Infect. Dis. 18, 341–345 (1999).
• Publication of practical relevance which
describes how a serological diagnosis of
pertussis can be made in a single
serum specimen.
43 Romano MJ, Weber MD, Weisse ME,
Siu BL. Pertussis pneumonia, hypoxemia,
hyperleukocytosis, and pulmonary
hypertension: improvement in oxygenation
after a double volume exchange
transfusion. Pediatrics 114, e264–e266
(2004).
44 Sawal M, Cohen M, Irazuzta JE et al.
Fulminant pertussis: a multi-center study
with new insights into the clinico-
pathological mechanisms. Pediatr.
Pulmonol. 44, 970–980 (2009).
• Provides insight in pathological findings
by autopsy in fatal cases of pertussis.
45 Zoumboulakis D, Anagnostakis D,
Albanis V, Matsaniotis. Steroids in
treatment of pertussis – a controlled
clinical trial. Arch. Dis. Child. 48, 51–54
(1973).
46 Tam AY, Yeung CY. Severe neonatal
pertussis treated by salbutamol. Arch. Dis.
Child. 61, 600–602 (1986).
47 Hoppe JE. State of art in antibacterial
susceptibility of Bordetella pertussis and
antibiotic treatment of pertussis. Infection
26, 242–246 (1998).
• Classical publication on the spectrum of
antibiotics that can be used for treatment
of pertussis; still relevant today.
48 Korgenski EK, Daly JA. Surveillance and
detection of erythromycin resistance in
Bordetella pertussis isolates recovered from a
pediatric population in the Intermountain
West region of the United States. J. Clin.
Microbiol. 35, 2989–2991 (1997).
49 Aoyama T, Sunakawa K, Iwata S,
Takeuchi Y, Fujii R. Efficacy of short-term
treatment of pertussis with clarithromycin
and azithromycin. J. Pediatr. 129, 761–764
(1996).
50 Langley JM, Halperin SA, Boucher FD,
Smith B, Pediatric Investigators
Collaborative Network on Infections in
171
 Review Heininger
Canada (PICNIC). Azithromycin is as
effective as and better tolerated than
erythromycin estolate for the treatment of
pertussis. Pediatrics 114, e96–e101
(2004).
51 Lebel MH, Mehra F, Mehra S. Efficacy
and safety of clarithromycin versus
erythromycin for the treatment of
pertussis: a prospective, randomized,
single blind trial. Pediatr. Infect. Dis.
J. 20, 1149–1154 (2001).
52 Hoppe JE and the Erythromycin Study
Group. Comparison of erythromycin
estolate and erythromycin ethylsuccinate
for treatment of pertussis. Pediatr. Infect.
Dis. J. 11, 189–193 (1992).
53 Bass JW, Harden LB. Treatment and
prophylaxis failure of erythromyin in
pertussis. Am. J. Dis. Child. 134,
1178–1179 (1980).
54 Halperin SA, Bortolussi R, Langley JM,
Miller B, Eastwood BJ. Seven days of
erythromycin estolate is as effective as
fourteen days for the treatment of
Bordetella pertussis infections. Pediatrics
100, 65–71 (1997).
55 Aoyama T, Sunakawa K, Iwata S,
Takeuchi Y, Fujii R. Efficacy of short-term
treatment of pertussis with clarithromycin
and azithromycin. J. Pediatr. 129,
761–764 (1996).
56 Centers for Disease Control.
Hypertrophic pyloric stenosis in infants
following pertussis prophylaxis with
erythromycin – Knoxville, Tennessee,
1999. MMWR 48, 1117–1120 (1999).
57 Honein MA, Paulozzi LJ, Himelright IM
et al. Infantile hypertrophic pyloric
stenosis after pertussis prophylaxis with
erythromycin: a case review and cohort
study. Lancet 354, 2101–2105 (1999).
58 Morrison W. Infantile hypertrophic
pyloric stenosis in infants treated with
azithromycin. Pediatr. Infect. Dis. J. 26,
186–188 (2007).
59 Hoppe J, Halm U, Hagedorn H,
Kraminer-Hagedorn A. Comparison of
erythromycin ethylsuccinate and
co-trimoxazole for treatment of pertussis.
Infection 17, 227–231 (1989).
60 Dodhia H, Crowcroft NS, Bramley JC,
Miller E. UK guidelines for use of
erythromycin chemoprophylaxis in
persons exposed to pertussis. J. Public
Health Med. 24, 200–206 (2002).
61 De Serres G, Boulianne N, Duval B. Field
effectiveness of erythromycin prophylaxis
to prevent pertussis within families.
Pediatr. Infect. Dis. J. 14, 969–975 (1995).
172
62 Halperin SA, Bortolussi R, Langley JM,
Eastwood BJ, De Serres G. A randomized,
placebo-controlled trial of erythromycin
estolate chemoprophylaxis for household
contacts of children with culture-positive
Bordetella pertussis infection. Pediatrics
104(4), e42 (1999).
63 Crameri S, Heininger U. Successful control
of a pertussis outbreak in a university
children’s hospital. Int. J. Infect. Dis. 12,
e85–e87 (2008).
64 Tozzi AE, Pandolfi E, Celentano LP et al.
Comparison of pertussis surveillance systems
in Europe. Vaccine 25, 291–297(2007).
65 Ward JI, Cherry JD, Chang SJ et al.
Efficacy of an acellular pertussis vaccine
among adolescents and adults. N. Engl. J.
Med. 353, 1555–1563 (2005).
• The only study until today which
demonstrated acellular pertussis vaccine
efficacy in adults.
66 Long S, Welkon C, Clark J. Widespread
silent transmission of pertussis in families:
antibody correlates of infection and
symptomatology. J. Infect. Dis. 161,
480–486 (1990).
67 Anderson RM, May RM. Immunisation
and herd immunity. Lancet 335(8690),
641–645 (1990).
68 Forsyth KD, Campins-Marti M, Caro J
et al. New pertussis vaccination strategies
beyond infancy: recommendations by the
global pertussis initiative. Clin. Infect. Dis.
39, 1802–1809 (2004).
69 Cherry JD, Baraff LJ, Hewlett E. The past,
present, and future of pertussis. The role of
adults in epidemiology and future control.
West. J. Med. 150, 319–328 (1989).
70 Cherry JD, Grimprel E, Guiso N,
Heininger U, Mertsola J. Defining
pertussis epidemiology: clinical,
microbiologic and serologic perspectives.
Pediatr. Infect. Dis. J. 24, S25–S34 (2005).
71 Pebody RG, Gay NJ, Giammanco A et al.
The seroepidemiology of Bordetella pertussis
infection in Western Europe. Epidemiol.
Infect. 133, 159–171 (2005).
72 Rota MC, D’Ancona F, Massari M et al.
How increased pertussis vaccination
coverage is changing the epidemiology of
pertussis in Italy. Vaccine 23, 5299–5305
(2005).
73 Hellenbrand W, Beier D, Jensen E et al.
The epidemiology of pertussis in Germany:
past and present. BMC Infect. Dis. 25, 22
(2009).
74 Cherry JD. Epidemiological, clinical, and
laboratory aspects of pertussis in adults. Clin.
Infect. Dis. 28 (Suppl. 2), S112–S117 (1999).
75 Hennes H. Der Keuchhusten bei
Erwachsenen. Med. Klinik. 17, 591–593
(1921).
76 Nelson JD. The changing epidemiology of
pertussis in young infants: the role of adults
as reservoirs of infection. Am. J. Dis. Child.
132, 371–373 (1978).
77 Mortimer EA. Pertussis and its prevention:
a family affair. J. Infect. Dis. 161, 473–479
(1990).
78 Heininger U, Stehr K, Christenson P,
Cherry JD. Evidence of efficacy of the
Lederle/Takeda acellular pertussis
component diphtheria and tetanus toxoids
and pertussis vaccine but not the Lederle
whole-cell component diphtheria and
tetanus toxoids and pertussis vaccine against
Bordetella parapertussis infection. Clin.
Infect. Dis.28, 602–604 (1999).
79 Trollfors B, Taranger J, Lagergard T et al. A
placebo-controlled trial of a pertussis-toxoid
vaccine. N. Engl. J. Med. 333, 1045–1050
(1995).
80 Greco D, Salmaso S, Mastrantonio P et al.
A controlled trial of two acellular vaccines
and one whole-cell vaccine against
pertussis. N. Engl. J. Med. 334, 341–348
(1996).
81 Gustafsson L, Hallander HO, Olin P,
Reizenstein E, Storsaeter J. A controlled
trial of a two-component acellular, a
five-component acellular and a whole-cell
pertussis vaccine. N. Engl. J. Med. 334,
349–355 (1996).
82 Schmitt HJ, Wirsing von König CH, Neiss
A et al. Efficacy of acellular pertussis
vaccine in early childhood after household
exposure. JAMA. 275, 37–41 (1996).
83 Simondon F, Preziosi MP, Yam A et al. A
randomized double-blind trial comparing a
two-component acellular to a whole-cell
pertussis vaccine in Senegal. Vaccine 15,
1606–1612 (1997).
84 Liese JG, Meschievitz CK, Harzer E et al.
Efficacy of a two-component acellular
pertussis vaccine in infants. Pediatr. Infect.
Dis. J. 16, 1038–1044 (1997).
85 Stehr K, Cherry JD, Heininger U et al. A
comparative efficacy trial in Germany in
infants who received either the Lederle/
Takeda acellular pertussis component DTP
(DTaP) vaccine, the Lederle whole-cell
component DTP vaccine or DT vaccine.
Pediatrics 101, 1–11 (1998).
86 Heininger U, Cherry JD. Pertussis
immunisation in adolescents and adults
– Bordetella pertussis epidemiology should
guide vaccination recommendations. Expert.
Opin. Biol. Ther. 6, 685–697 (2006).
Expert Rev. Anti Infect. Ther. 8(2), (2010)

•• Complements this review owing to its
specific focus on adolescents and adults.
87 Collins CL, Salt P, McCarthy N et al.
Immunogenicity and safety of a low-dose
diphtheria, tetanus and acellular pertussis
combination vaccine with either inactivated
or oral polio vaccine as a pre-school booster
in UK children. Vaccine 22, 4262–4269
(2004).
88 Minh NN, He Q, Ramalho A et al.
Acellular vaccines containing reduced
quantities of pertussis antigens as a booster
in adolescents. Pediatrics 104, e70 (1999).
89 Cherry JD. ‘Pertussis vaccine
encephalopathy’: it is time to recognize it as
the myth that it is. JAMA 263, 1679–1680
(1990).
• Concise summary on the issue of the
nonexistence of a causal relationship
between pertussis immunization
and encephalopathy.
90 Heininger U, Zuberbühler M.
Immunization rates and timely
administration in pre-school and school-
aged children. Eur. J. Pediatr. 165,
124–129 (2006).
91 Elomaa A, He Q, Minh NN, Mertsola J.
Pertussis before and after the introduction
of acellular pertussis vaccines in Finland.
Vaccine 27, 5443–5449 (2009).
www.expert-reviews.com
Update on pertussis in children Review
92 Juretzko P, von Kries R, Hermann M, 97 Van Rie A, Wendelboe AM, Englund JA.
Wirsing von König CH, Weil J, Giani G. Role of maternal pertussis antibodies in
Effectiveness of acellular pertussis vaccine infants. Pediatr. Infect. Dis. J. 24(Suppl.),
assessed by hospital-based active S62–S65 (2005).
surveillance in Germany. Clin. Infect. Dis. 98 de La Rocque F, Grimprel E, Gaudelus J
35, 162–167 (2002). et al. Vaccination in parents of young
93 Heininger U, Cherry JD, Stehr K et al. infants survey. Arch. Pediatr. 14,
Comparative efficacy of the Lederle/ 1472–1476 (2007).
Takeda acellular pertussis component
DTP (DTaP). vaccine and Lederle
whole-cell component DTP vaccine in Website
German infants following household
101 WHO Vaccine Preventable Diseases
exposure. Pediatrics 102, 546–553 (1998).
Monitoring System
94 Halasa NB, O’Shea A, Shi JR, LaFleur BJ, www.who.int/vaccines/globalsummary/
Edwards KM. Poor immune responses to a Immunization/CountryProfileSelect.cfm
birth dose of diphtheria, tetanus, and (Accessed September 28 2009)
acellular pertussis vaccine. J. Pediatr. 153,
327–332 (2008).
Affiliation
95 Knuf M, Schmitt HJ, Wolter J et al.
Neonatal vaccination with an acellular • Ulrich Heininger, MD
University Children’s Hospital (UKBB),
pertussis vaccine accelerates the acquisition
PO Box, CH-4005 Basel, Switzerland
of pertussis antibodies in infants. J. Pediatr.
152, 655–660 (2008). Tel.: +41 616 856 565
Fax: +41 616 856 012
•• Shows that newborns can be immunized
ulrich.heininger@ukbb.ch
effectively against pertussis.
96 Heininger U, Cherry JD, Christenson P
et al. Comparative study of Lederle/Takeda
acellular and whole-cell pertussis
component diphtheria-tetanus-pertussis
vaccines in infants in Germany. Vaccine 12,
81–86 (1994).
173