Pertussis: review of epidemiology, diagnosis,management and prevention

Nicholas Wood* and Peter McIntyre

National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, The ChildrensHospital at Westmead and the University of Sydney, New South Wales, Australia

PAEDIATRIC RESPIRATORY REVIEWS (2008) 9, 201212

EDUCATIONAL AIMS

To understand the current epidemiology of pertussis and recent changes in the burden of disease. To appreciate the different clinical presentations of pertussis in infants and adolescents. To understand the sensitivity, specificity and limitations of available laboratory investigations to diagnose pertussis

infection. To understand antibiotic use in the treatment of pertussis and groups for whom prophylactic treatment is

recommended. To understand the rationale underlying the different vaccination strategies for prevention of pertussis infection.

KEYWORDS

pertussis;

Summary Bordetella pertussis the cause of pertussis or whooping cough is anexclusively human pathogen. Disease elimination by vaccination should, therefore, beBordetella pertussis the cause of pertussis or whoopingcough is an exclusively human pathogen.1 Disease elim-ination by vaccination should, therefore, be possible, buthas proved elusive. Soon after whole cell pertussis vaccineswere introduced in industrialised countries from the late

* Corresponding author. National Centre for ImmunisationResearch and Surveillance of Vaccine Preventable Diseases(NCIRS), Locked Bag 4001, Westmead, NSW 2145, Australia.Tel.: +61 2 9845 1429; Fax: +61 2 9845 1418.

E-mail address: nicholw3@chw.edu.au (N. Wood).

clinical presentation;

epidemiology;

treatment;

prevention;

vaccination strategies

possible, but has proved elusive. Many industrialised countries with long establishedimmunisation programs are currently seeing a resurgence of pertussis, despite universalvaccination with high uptake, with the highest burden in the least immunised age groups(infants under 6 months of age and persons over 10 years old). However, low recognitionand reporting and insensitive diagnostic tests mean that the true burden of pertussis is stillunderestimated. Recently, efforts to improve diagnostic yield include the expanded use ofpolymerase chain reaction and serological tests but both have significant limitations. Therange of antibiotics available for treatment and prophylaxis has expanded to include thenewer macrolides, azithromycin and clarithromycin, and a range of universal and targetedvaccination strategies have been implemented or proposed. This paper reviews thecurrent epidemiology of pertussis in developed countries, including modes of clinicalpresentation, diagnosis, management and potential vaccination strategies.Crown Copyright 2008 Published by Elsevier Ltd. All rights reserved.

1526-0542/$ see front matter . Crown Copyright 2008 Published by Elsevier Ltd. All rights reserved.CME ARTICLEdoi:10.1016/j.prrv.2008.05.010

of

nature of the organism and the limited period during

ple, in Brazil, no increase in pertussis was documented

many industrialised countries.5,1417 In countries with well-

pertussis in infants under 4 months of age increased from

202 N. WOOD AND P. MCINTYREwhich even meticulous practice can yield a positiveculture, particularly in vaccinated persons. Recent effortsto improve the accuracy of diagnosis include increaseduse of PCR and single high titre pertussis serology.However, both have significant limitations. The oftenpoor tolerance and therefore compliance with traditionalmacrolide therapy for treatment and prophylaxis ofpertussis, as well as doubts about its efficacy, has ledto clinical trials with the newer macrolides, clarithromycinand azithromycin.8,9

This review will examine:

current epidemiology of pertussis and recent changes inthe burden of disease

clinical presentations in infants and adolescents diagnostic methods treatment and prophylaxis vaccination strategies for prevention.

EPIDEMIOLOGY OF PERTUSSIS

Surveillance of pertussis in most countries is based onclinical notifications and laboratory reports. In developedcountries with long-established vaccine programs, thegeneral trend has been for increasing incidence with ashift to infection in older persons, although the highestincidence continues to be in infants too young to beeligible for vaccination. Comparison of pertussis inci-dence between countries is problematic due to differ-ences in case definitions, access to diagnostic tests,clinician awareness and reporting practices and whetherpertussis is notifiable under public health legislation.Differences in immunisation strategies and historicalspeleB. pertussis still the gold standard for diagnosticcificity has always been hampered by the fastidiousboth developed and less developed countries.6,7 Culture

than reported by either notifications or hospitalisations in

pertussis is generally considered to be substantially higher

clindiagnostic test sensitivity, even for newer tests, such aspolymerase chain reaction (PCR). This is particularly truefor older populations with less typical and often later

ical presentation. Currently, the true incidence of1940s there was a marked decline in reported pertussisdisease.1 However, despite universal vaccination programswith high uptake, many industrialised countries, includingthe United States, France, Canada and Australia, have had asignificant resurgence of notified pertussis in the pastdecade, particularly among adolescents and adults.25

In adults and older children, the diagnosis of pertussisis often delayed because of lack of classic symptoms and/or low physician awareness, resulting in the potential totransmit infection for several weeks.1 The true incidenceof pertussis is poorly defined because of varying levels ofclinician suspicion and reporting practices and limitedvels of immunisation coverage within and between63.4 cases per 100 000 in the 1980s to 88.7 cases per 100000 in the 1990s.15 From 2001 to 2003, the highest annualincidence was in infants under 6 months of age (98.2 per100 000), compared with 12.3 per 100 000 in infants aged611 months.21 In European countries the highest inci-dence rates are also in infants but are not increasing.2224 Indeveloped immunisation programs, such as the UnitedStates, Australia and Canada, pertussis is now a problemin two broad age groups those over the age of 10 yearsand those under the age of 5 months.3,15,16,18,19 The formergroup were often born in an era of low immunisationcoverage, with waning immunity in those who were vacci-nated while the latter cannot be fully protected by currentvaccine schedules.

Pertussis in infancy

Rates of pertussis infection remain highest in infants, espe-cially under the age of 6 months (Table 1). In New SouthWales, Australia, a significant reduction in pertussis-relatedhospitalisations in the most highly vaccinated age group (5months to 9 years) was documented but hospitalisationsfor pertussis under the age of 5 months remainedunchanged.20 In the US, the mean annual incidence offollowing introduction of pertussis vaccination in the1980s11 and in Argentina, few epidemiologic studiesare available.12 Despite these constraints, it is clear thatpertussis remains one of the top 10 causes of death inchildren under 1 years old worldwide with an estimated10 million cases and as many as 400 000 pertussis-relateddeaths annually, 90% in developing countries and mostlyin infants.7,13,14

Developed countries

A resurgence of pertussis has been well documented incountries also affect the epidemiology of pertussis. Clin-ical recognition of disease due to B. pertussis infection isoften poor, especially in adults and older children, whoare more likely to present with atypical findings, on abackground of waning immunity from infection or priorvaccination.

Developing countries

Recent reports of pertussis epidemiology from Asia,Africa and South America are limited but World HealthOrganization (WHO) estimates demonstrate that thesecountries have the highest disease burden.7,10 Estimatingrates of pertussis is difficult, because of lack of access todiagnostic methods, misdiagnosis, under-reporting, anddifferent reporting criteria between countries. For exam-Canada, 89% of infants admitted with pertussis to tertiary

incidence of pertussis infection (defined serologically) in duration of protection and waning immunity following

A REVIEW OF PERTUSSIS 203

ge

spits (p

8

(05 (6.6

6 (6.7

(0(3(6

2adolescents and adults is around 1% per year (range 0.42.7%)29 while the estimated annual incidence of sympto-hospitals between 1991 and 2001 were under the age of 6months with most deaths under 3 months of age.18

Pertussis in older children and adolescents

In Europe, the surveillance project EUVAC-NET hasrecorded a 115% increase in incidence rates in children agedover 14 years between 1998 and 2002.23 Increased pertussisincidence in adolescents (aged 1019 years) has also beendocumented in the US, from 5.5 per 100 000 in 2001 to 10.9per 100 000 in 2003.21 Data from the Acellular Pertussisvaccine trial (APERT) conducted in the US suggest that the

Table 1 Pertussis hospitalisation rates in infants

to increased notification rates for pertussis.14 A recentstudy in Toronto, Canada, reports that a marked increasein pertussis incidence in 2006 was associated with amarkedly increased volume of tests performed, primarilyPCR-based assays.51 Increased press reports and scientificliterature on the resurgence of pertussis, as well asreports of pertussis vaccine trials and subsequent licen-sure of low dose acellular pertussis vaccines for use inadults, may have also led to an increase in clinicianawareness and reporting.52 However, in many developingand some developed countries, identification of pertussisis still limited by patient and physician awareness and thelimited sensitivity of diagnostic tests.6 In infants, increasedrates of pertussis may be related to both changes invaccination strategies and infection sources as well asthe availability of PCR as a diagnostic tool.

DIAGNOSIS

nised infants) and awareness of clinicians. The sensitivity and

204 N. WOOD AND P. MCINTYRE

Table 2 Clinical management algorithmIncomplete protection from vaccination

Two or more doses of a pertussis-containing vaccineappear to be needed for protection.31,39 Infants under 5months old are too young, under most immunisationschedules, to have reliably received two or more doses.In Australia, half of all pertussis hospitalisations between1994 and 2004 occurred in infants under 12 weeks of age,eligible to receive only one dose of pertussis-containingvaccine at 8 weeks of age.40 In a multinational study,approximately 75% of hospitalised infants had receivedno or one dose only of pertussis vaccine.41

Infection source for infants

Adults, particularly parents, are the most important source ofinfection for infants.8,9,41 Individuals with pertussis disease aremost infectious during the initial catarrhal period and for thefirst 2 weeks of spasmodic cough, but can remain infectiousfor up to 6 weeks, especially in the case of non-immuneinfants.42 A probable scenario is that adults and adolescents,who become infected because of waning vaccine or disease-induced immunity, act as reservoirs for infection and transmitinfection to unvaccinated or partially vaccinated infants.14 InAustralia, a national study identified a presumptive source ofinfection in 60% of 110 hospitalised infants, of whom 60%were parents.43 Parents were also identified as a commoninfection source in a French hospital-based study.5 In ahousehold transmission study in Brazil, three-quarters ofinfants under 6 months of age were infected by people over11 years old.44 In addition to parents, other adults in closecontact with young infants such as grandparents and health-care workers can be responsible for transmission.8,43,45,46

Infection source for adolescents

School outbreaks have been documented in both the USand Australia as significant markers of transmission ofpertussis among adolescents.47,48

Strain polymorphism

It has been suggested that B. pertussis has adapted toexpress PT and pertactin (PRN) strains distinct from thevaccine strains, with consequent reduction in vaccine effec-tiveness, especially in the Netherlands and Finland.16,48,49

Recent studies in Finland have noted that B. pertussis hasdocumented conformational changes in one region of PRNand suggested that reduced vaccine-induced immunity tothis strain may account for increased pertussis infection.49,50

However, despite evidence of polymorphism for PT andPRN in several countries, no direct link to vaccinationprograms or their efficacy has been proved.16

Increased diagnosis and reporting

In developed countries it is likely that improved diagnostic

techniques and reporting has made a major contributionClinical suspicion of pertussis Coughing illness more than 2 weeks (or cough of any

duration with contact with a confirmed case) Paroxysms Inspiratory whoop Post-tussive vomiting

Epidemiological links One person in chain of contact likely to be infectious

(from catarrhal stage to 3 weeks after onset of cough) Laboratory evidence of pertussis in one of the cases Second person has onset of illness within 620 days

after contact

Laboratory investigation If 3 weeks since cough onset consider pertussis toxin

IgG if availablespecificity of laboratory tests is influenced by the use ofantibiotics early in the course of infection, mixed infections,recent immunisation and time since symptom onset, as wellas inherent limitations in insensitivity.14,22,53

22,74The identification and clinical management of pertussisrequires a combination of clinical suspicion, appropriatelaboratory tests and consideration of antibacterial therapy(see algorithm in Table 2).

Clinical diagnosis

Suspicion of pertussis may be prompted by clinical signs andsymptoms or by a history of exposure to a confirmed case.Clinical diagnosis is problematic because of the widespectrum of disease manifestations (both in those withpartial immunity due to past vaccination and in unimmu-

more common in children with serologic evidence of

Culture is considered to be the gold standard, however, its

Antibodies to different pertussis antigens PT, PRN,

convalescent sera (4 weeks post acute sera measurement)

A REVIEW OF PERTUSSIS 205duration of cough in adults with pertussis is 3648 days and itmay be only nocturnal.56 Adults and adolescents usuallypresent late in the course of the infection, often after 4 ormore weeks of coughing,52,57 although diagnostic delay byclinicians is also frequent.58 Complications in adults can alsopresthebes been found to be the cause in 1320% of adultsenting with prolonged cough, although the nature ofreferral population differs among studies.22 The meanhistohaMost cases of adult pertussis occur in those who have ary of past pertussis vaccination or infection.56 Pertussischildwere significantly less likely to be completely vaccinatedaccording to the UK schedule (86% vs. 97% of seronegative

ren).pertussis infection, and wheeze significantly less common,whoop was present in 25% of seronegative children andparoxysmal coughing in 75%. Coughing severity was greaterin the seropositive group among whom 85% were stillcoughing 2 months later and significantly more had parentswith sleep disturbance. It is important to note that childreneligible for this study would have received their last dose ofpertussis vaccine at 4 months of age but the UK now has abooster dose at 4 years. Despite this, seropositive childrenChildren

Children are more likely to experience classical pertussis,with an incubation period of 710 days (range 521 days),followed by three phases of illness:

catarrhal non-specific prodromal coryzal illness, mildcough, lasting 12 weeks

paroxysmal spasmodic cough, post-tussive vomitingand inspiratory whoop lasting 46 weeks

convalescent symptoms slowly improving over 12weeks.

Complications are more common in non-immuneinfants. These include pneumonia, failure to thrive frompost-tussive vomiting, seizures, encephalopathy, cerebralhypoxia, secondary bacterial infection, pulmonary hyper-tension, sub-conjunctival haemorrhage and rectal pro-lapse.22 Very young infants may initially present withapnoea alone. Most deaths from pertussis are in childrenunder 6 months old, particularly in those under 1 month ofage.54

Older children, adolescents and adults

Pertussis infection in older children, adolescents and adultscan range from classic pertussis to mild or no cough.29 In arecent UK study, 37% of consecutive children, aged 516years, presenting to primary care with cough for more than14 days had serological evidence of pertussis on well-standardised tests but culture or PCR were not routinelyperformed.55 While whoop and vomiting were significantlysevere including: hospitalisation, inguinal hernia, fracturedare obtained, however, serology is frequently used todiagnose infection late in the course of illness when acutesera have not been obtained. Serology, especially serumfilamentous haemagglutinin (FHA), fimbrial proteins andwhole organism appear following natural infection.Increases in anti-PT IgG and anti-FHA IgG are measurablein over 90% of infections, anti-PRN IgG in 3060%, anti-PRN IgA in 2040%, anti-PT IgA in 2040% and anti-FHAIgA in 3050% of infected persons.60 However, the anti-body cut-off that defines a diagnosis of pertussis is deba-table and somewhat test-dependent. The sensitivity ofserologic tests tends to be lower than their specificity,ranging from 20%61 to 90%62 compared with culture and/or PCR.

Ideally acute sera (

and/or PCR.62 Pebody et al. reported that a single serum

less of their age and immunisation status. In the UK and

206 N. WOOD AND P. MCINTYREmean anti-PT IgG antibody level equivalent to 125 ESEN U/mL was consistent with pertussis infection within sixmonths of sample collection, while a level of >62.5 ESENU/mL was consistent with infection within the past year.34

Currently only Australia, Finland and the Netherlandsinclude serology based on single anti-IgA and/or anti-IgGantibody measurements in national pertussis notificationdata, in the former two using whole-cell based assays and inthe Netherlands IgG to PT.13,22,62,64

PCR

PCR is more sensitive than culture by 2- to 3-fold in patientswho present after 3 weeks of coughing or commencementof antibiotic therapy.13,65 Reported sensitivities range from73% to 100%.22,66 However, there is no inter-laboratorystandardisation of PCR, with over 100 different PCR pro-tocols reported, differing in DNA purification techniques,PCR primers, reaction conditions and product detectionmethods.53 The specificity of PCR can be reduced bycontamination in the laboratory or at the time of specimencollection, such as false-positive PCR in patients with upperrespiratory tract colonisation with Bordetella holmesii.53,67,68

PCR does not cross react with Bordetella parapertussis asthis organism does not contain PT. The Center for DiseaseControl and Prevention (CDC) recommends that PCR beused to support the diagnosis of pertussis when the casemeets the clinical case definition of 2 or more weeks ofcough associated with paroxysms, whoop or post-tussivevomiting. However, strict application of this approachexcludes contacts with no or lesser duration of symptomswhere utility of PCR for diagnosis may be higher. PCR ismost useful in older children and adults, as delayed pre-sentation makes other diagnostic methods such as cultureand PCR less likely to be positive.63 As most adolescentsand adults are partially immune from previous vaccinationor infection, ideally two samples are needed to demon-strate a rise in antibody titre. The most specific serologictest is IgA or IgG to PT because it is unique to B. pertussisand decays to below cut-off levels most rapidly postinfection, with an average of 4.5 months and in 82% ofcases within 1 year of infection.13,22,29 For this reason, asingle high IgG to PT has been used as a marker of acutepertussis infection with estimates of 76% and 99% forsensitivity and specificity respectively. In contrast,enzyme-linked immunoabsorbent assay tests that measureantibodies to whole pertussis antigens are less sensitive andspecific.52

Diagnosis based on single titre serology is more clinicallyuseful. Investigators from the Netherlands found that asingle serum with an anti-PT IgG of greater that 100 Dutchunits/mL was indicative of recent (within 4 weeks) infectionwith B. pertussis proven by either a fourfold or higherchange in the acute and convalescent sera, positive cultureparticularly useful in infants where pertussis is suspected asAustralia, more limited recommendations for treatmentof contacts are made in view of the limited effectivenessserology is not applicable and specimens are more easilytransported and more rapidly reported than for culture.

MANAGEMENT

Acute pertussis infection

Infection in infants under 6 months old may require hospi-talisation for supportive care of complications, for exampleapnoea, hypoxia or feeding difficulties. Treatment withantibiotics does not significantly shorten the clinical coursein infected patients but aims to reduce transmission toother persons. In the past, erythromycin was the first-lineantibiotic for pertussis treatment but it was associated withsignificant adverse effects including hypertrophic pyloricstenosis in infants and cardiac arrhythmias (QT prolonga-tion and ventricular arrhythmias). A recent Cochranereview recommended the use of azithromycin and clari-thromycin as first-line antimicrobial agents.69 This is alsosupported by data from a multi-centre randomised trial inNorth America, where azithromycin was shown to be aseffective as erythromycin, better tolerated and associatedwith improved compliance.70 The US CDC recommendsthat azithromycin should be used for all neonates under 1month,71 with erythromycin, clarithromycin or azithromy-cin acceptable for the treatment of pertussis in personsaged1 month. Resistance to azithromycin has been rarelyreported. For treatment of persons aged 2 months, analternative agent if there is allergy or intolerance to macro-lides is trimethoprim-sulfamethoxazole (TMPSMZ)although effectiveness is less well documented. Erythro-mycin and clarithromycin are inhibitors of the cytochromeP450 enzyme system (CYP3A subclass) and can interactwith other drugs metabolised by this system. Azithromycinand clarithromycin are more resistant to gastric acid,achieve higher tissue concentrations, and have a longerhalf-life than erythromycin, allowing less frequent adminis-tration (12 doses per day) and shorter treatment regi-mens (57 days), with likely improved adherence totherapy. Roxithromycin is another macrolide antibiotic.However, there are no clinical studies on its effectivenessin pertussis, and in-vitro sensitivity studies suggest it may beinferior to erythromycin so it is not currently recom-mended for treating pertussis.71 Table 3 summarises themost common antibiotics used to treat acute pertussis andtheir regimen.

Prophylaxis

Macrolide antibiotics have been recommended for treat-ment of contacts within 3 weeks of onset of disease. Inthe US, contacts include all household members, andother close contacts, such as childcare attendees, regard-of chemoprophylaxis, focussing on those at most risk of

complications.72,73 This includes any infant who hasreceived less than three doses of DTPa, any womanin the last month of pregnancy and any child or adult whoworks/attends a healthcare or childcare facility.

Pertussis-containing vaccines should be given if due atthe time of exposure or the course commenced in thosewho are unimmunised or not completely immunised. The

manufacturers include PT and PRN as sub-studies from Paefficacy trials have implicated PT and PRN, but not FHA, inprotection76 and lead to the conclusion that PT and PRNIgG antibodies are the current best surrogate for protec-tion. In many countries pertussis antigens are now includedin multivalent vaccines, which may contain diphtheria,tetanus, hepatitis B, Haemophilus influenzae type B, and

A REVIEW OF PERTUSSIS 207

78

Table 3 Antibiotics used to treat acute pertussis and their regimen 74,87

Erythromycin Azithromycin Clarithromcyin Trimethoprim-sulfamethoxazole

Dose 4050 mg/kg/day 1012 mg/kg/day 1520 mg/kg/day 8 mg/kg/day (TMP)10 mg/kg on day 40 mg/kg/day (SMX)1 then 5 mg/kg on days 25

maximum 2 g/day maximum 500 mg/day maximum 1 g/dayInterval 4 divided doses daily 2 divided doses 2 divided dosesDuration 14 days 5 days 7 days 14 daysCURRENT VACCINE STRATEGIESFOR PREVENTION

Vaccines using inactivated whole B. pertussis organisms(Pw) of three serotypes were first developed in the1930s and subsequently combined with diphtheria andtetanus toxoids for widespread use in immunisation pro-grams.75 In many industrialised countries currently acellularpertussis vaccines (Pa) that include up to five antigens, (PT,FHA, PRN and two different fimbrial proteins) are used. All

Table 4 Pertussis vaccination schedules in selected countries

Country/Organisation Type of pertussis containingvaccine

WHO DTPwAustralia DTPa-combinationRedbook 2006 recommends that children who havereceived their third dose more than 6 months prior tothe exposure receive a fourth dose at the time of exposure.Children under 7 years of age who have had four doseswhere the last dose was more than 3 years before theexposure should also be given a DTPa vaccine. Nationalguidelines from the UK and Australia also recommendDTPa vaccines be given to unvaccinated or partially vacci-nated children who are contacts up to their 8th (Australia)or 10th (UK) birthday.72,73Brazil DTPw-combinationCanada DTPa-combinationEgypt DTPw-combinationFrance DTPa-combinationGermany DTPa-combinationItaly DTPa-combinationSouth Africa DTPw-combinationSweden DTPa-combinationUK DTPa-combinationUSA DTPa-combination

Available at: http://www.who.int/immunization/en/.Potential strategies to address continuingpertussis in early infancy

Pertussis vaccination schedules differ significantly aroundthe world but none currently start earlier than 6 weeks ofage (Table 4). The WHO recommends a schedule of 6, 10and 14 weeks for primary immunisation against pertussis.78

Re-evaluation of pertussis vaccination schedules is apriority given the resurgence of pertussis in very younginfants and in those aged over 10 years. The Global

Primary immunisationschedule

Adolescent dTp boosterrecommended

6, 10, 14 weeks No2, 4, 6 months Yespoliovirus.Recently, a low dose, adult-formulated diphtheria, teta-

nus, acellular pertussis (dTpa) vaccine has been licensedand recommended in several countries, including the USA,Australia, Canada, France, Germany and Switzerland, foruse in adults and adolescents. Efficacy data from a large trialin the USA (APERT), estimates vaccine protection fromculture or PCR proven symptomatic pertussis disease is92%, although protection against less severe coughing ill-ness is likely to be only 5060%.772, 4, 6 months No2, 4, 6 months Yes2, 4, 6 months No2, 3, 4 months Yes3, 4, 5 months Yes3, 5, 11 months No6, 10, 14 weeks No3, 5, 12 months Yes2, 3, 4 months No2, 4, 6 months Yes

tussis vaccines could be administered to infants earlier than

Italian schedule for DTPa vaccination at 3, 5 and 11

burden on pertussis is not known, access to new diag-

resource poor settings is needed. In addition, improve-

208 N. WOOD AND P. MCINTYREmonths.81 Second, a US study compared DTPa adminis-tered at birth in 50 term infants with the standard vaccina-tion schedule. Pertussis antibody levels were similar at 6months of age in the two groups, but at 7 months levelswere significantly lower in the group vaccinated at birth,suggesting that birth vaccination may result in earlier anti-body loss and that additional boosters may be requiredafter 6 months.82 Third, a German study found Pa vaccineat birth resulted in a significantly higher response to68 weeks old. There are three reported human studies,only two published, reporting the effect of Pa vaccination atbirth.8183 First, an Italian study showed that a birth dose ofPa vaccine followed by doses containing the same amountsof pertussis antigens at ages 3, 5 and 11 months, resulted inearlier antibody responses compared with the standardThere is good evidence that parents are the most commonsource of infection for infants14,43 and that dTpa boostervaccine given to parents can prevent or reduce adultinfection rates. In Australia, France, Germany, the USAand Austria it is recommended that all parents of newbornsreceive a dTpa booster shortly after delivery of their child.Modelling has demonstrated that a combination of routineadult vaccination every 10 years commencing at age 20years and selective vaccination of household contacts ofnewborns would result in the greatest reduction in infantpertussis incidence.79 Another modelling study suggestedthat the combination of a cocoon strategy and a single dosefor all adults might be easier to implement than recurrentdoses for adults.80

Earlier infant and neonatal immunisation

Recently attention has turned to whether acellular per-Pertussis Initiative (GPI) a multidisciplinary panel ofexperts created in 2001 recently evaluated seven poten-tial pertussis vaccine strategies.6,8 These strategies, whichare not mutually exclusive, include: universal adult and/oradolescent vaccination; indirect protection of infants byimmunisation of parents and possibly others in close con-tact with the newborn, such as grandparents and healthcareworkers; infant and early infant immunisation (from birth to1 month of age); and maternal immunisation.

Adult/adolescent vaccination

A reduction in the adult/adolescent reservoir could beachieved by administering a booster dose of DTpa. Uni-versal vaccination for adolescents is recommended inseveral countries (Table 4).

Indirect protection of infants through parentalvaccinationpertussis antigens at 3 months of age compared withments in the sensitivity and specificity of laboratorydiagnostic methods, technology transfer to resourcepoor settings, could result in earlier more accuratediagnosis, earlier commencement of treatment andreduced transmission. One of the UN Millennium Devel-opment Goals is to reduce child mortality by one-thirdby 2015 and includes the necessity to reduce pertussisnostic methods, such as PCR, is non-existent and pro-blems with vaccine availability result in low coverage insome areas, although overall global coverage for threedoses of pertussis vaccine has now reached 80%.Attempts to improve vaccine coverage through interna-tional groups, such as the Gates Foundation, and newermethods of financing (International Financing Facility) willassist in improving coverage. However, measuring theimpact of vaccination on reducing pertussis disease bur-den will require high quality epidemiological data andsupport for the development of monitoring systems incontrols but no difference at 7 months of age.83 Nosignificant adverse events were reported following neo-natal Pa vaccination in these three studies, however neo-natal vaccination may be associated with potentialalterations in immune responses to other vaccine antigens(diphteria, tetanus, Hepatitis B) co-administered with thePa vaccine.

Maternal vaccination during pregnancy

Maternal vaccination has been extremely successful inpreventing neonatal tetanus in developing communities.Maternal pertussis immunisation is a possible strategy forprevention of infant infection, because active placentaltransfer of pertussis specific antibodies to the foetus occursand has been recently reviewed.84 No studies evaluatingantibody response or protection following maternal vacci-nation with acellular pertussis vaccines in pregnancy arecurrently available.

INTERNATIONALCOLLABORATIONS

International collaborative efforts to address the risingincidence of pertussis have commenced. The GPI wascreated in 2001, following an educational grant fromSanofi Pasteur, and includes over 30 scientific expertsfrom 17 countries who were divided into three regionalsubgroups Europe, North America and International.The focus of this group is to raise global awareness ofpertussis as an important preventable disease and todevelop and communicate evidence-based recommen-dations for immunisation based strategies to slow theincreasing trend in pertussis incidence.85 For manyresource-poor settings, an accurate estimate of the truedeaths.

CONCLUSION

Globally, pertussis remains a challenge in both developingand developed countries. In both settings, infants under 5months of age have the highest rates of pertussis disease,morbidity and death. In developed countries widespreaduniversal vaccination of infants has dramatically decreasedthe incidence of pertussis, especially hospitalisation anddeath, among those aged 110 years, but the burden ofdisease has shifted to older ages with adolescents andadults now most likely to transmit pertussis to a younginfant. In developing countries, high coverage for threedoses of pertussis-containing vaccines at 6, 10 and 14weeks remains the key challenge and transmission fromolder children is still the primary issue. The managementof suspected pertussis requires a combination of clinicalsuspicion, laboratory tests based on age and clinicalhistory, antibacterial therapy for cases and, where appro-priate, for contacts. PCR and single titre serology aremore useful than culture when confronted with patientscoughing for 13 weeks (PCR) and for more than 3 weeks(serology) or in those with preceding antibiotic therapy.Antibacterial therapy makes a minimal contribution to thecontrol of pertussis, with better and wider use of vaccinesthe most important strategy in developed and developingcountries.

A REVIEW OF PERTUSSIS 209KEY POINTS

In countries with well-developed immunisation pro-grams, symptomatic pertussis infections are nowpredominantly in the least well-immunised groups(over the age of 10 years and under 5 months).

In adults and older children, diagnosis of pertussis isoften delayed because classic symptoms are fre-quently absent, resulting in the potential to transmitinfection for several weeks.

The sensitivity of laboratory tests for pertussis isreduced by the use of antibiotics early in the courseof infection, mixed infections, delay in presentationand/or diagnosis inherent limitations. Available testsare predominantly serology, PCR and culture: nasopharyngeal swab for culture and/or PCR has

highest yield 3 weeks

serologic tests are best standardised for IgG to PT;single titre serology only feasible diagnostic test 3or more weeks after cough onset.

Antibiotic treatment does not significantly shorten theclinical course in infected patients but aims to reducetransmission to other persons. Azithromycin is theagent of choice but expensive.REFERENCES

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A REVIEW OF PERTUSSIS 211CME SECTION

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Educational questions

Answer true or false to the following questions:

1. With regard to the current epidemiology of pertussisin countries with well-developed immunisation pro-grams:a. Pertussis infection is predominant in children aged

15 years old.b. The high rates in adolescents and adults are

primarily due to waning immunity.c. Infants under 5 months old are reliably protectedfrom pertussis infection by current vaccinationschedules.

d. Individuals with pertussis disease are most infec-tious when spasmodic cough is established.

e. Polymorphism of pertussis genes is induced byvaccination programs and the main cause of therising pertussis incidence.

f. Pertussis has been found to be the cause in upto 20% of adults with prolonged cough incountries with well-developed immunisationprograms.

2. With regard to the diagnosis of pertussis:a. The sensitivity of culture increases steeply if the

specimen is taken more than 2 weeks after onsetof cough.

b. Sensitivity of culture is increased with the use ofswabs taken by the pernasal route.

c. The most specific serologic test is IgA or IgG toPT, which is unique to B. pertussis.

d. A single IgG titre to PT has a sensitivity ofapproximately 75% for acute pertussis infection.

e. PCR is less sensitive than culture in patientswho present after commencement of antibiotictherapy.

212 N. WOOD AND P. MCINTYRE

f. False-positive PCR can occur in patients withupper respiratory tract colonisation with Borde-tella holmesii.

3. Pertussis treatmenta. Treatment with antibiotics shortens the clinical

course in infected patients by about 2 weeks.b. Azithromycin and clarithromycin are currently

recommended as the first-line antimicrobialagents.

c. An advantage of erythromycin is improved com-pliance due to a reduced duration of therapy.

d. Alternative agent to macrolides is trimethoprim-sulfamethoxazole (TMPSMZ) in the case ofallergy or intolerance.

e. Macrolide antibiotics have been recommendedfor treatment of contacts within 8 weeks of onsetof disease in the case.

f. Pertussis containing vaccines should be given ifdue at the time of exposure or the course

commenced in those who are incompletelyimmunised.

4. With regard to pertussis vaccination strategies:a. Currently, acellular pertussis vaccines (Pa) all

include the antigens PT, FHA, and fimbrial endo-toxin.

b. Estimates of vaccine protection from low dosedTpa booster vaccine in adults are over 90%for culture or PCR proven symptomatic per-tussis.

c. Parents of newborn infants are recommended toreceive a booster dose of low dose dTpa vaccine.

d. Neonatal administration of acellular pertussis vac-cine is now routinely recommended in severalcountries.

e. Women should never receive dTpa vaccine whilepregnant.

f. National guidelines on vaccination regimens exist inmany countries and are available for clinician use.

Pertussis: review of epidemiology, diagnosis, management and preventionEducational AimsEpidemiology of pertussisDeveloping countriesDeveloped countriesPertussis in infancyPertussis in older children and adolescents

Possible explanations for current epidemiologyDuration of protection and waning immunity following infection and vaccinationIncomplete protection from vaccinationInfection source for infantsInfection source for adolescentsStrain polymorphismIncreased diagnosis and reporting

DiagnosisClinical diagnosisChildrenOlder children, adolescents and adults

Laboratory testsCultureSerologyPCR

ManagementAcute pertussis infectionProphylaxis

Current vaccine strategies for preventionPotential strategies to address continuing pertussis in early infancyAdult/adolescent vaccinationIndirect protection of infants through parental vaccinationMaternal vaccination during pregnancy

International collaborationsReferencesKey pointsCME SectionEducational questions