Elsevier

Vaccine

Volume 29, Issue 6, 1 February 2011, Pages 1115-1121
Vaccine

Conference report
The Global Pertussis Initiative: Report from a Round Table Meeting to discuss the epidemiology and detection of pertussis, Paris, France, 11–12 January 2010

https://doi.org/10.1016/j.vaccine.2010.12.010Get rights and content

Abstract

Pertussis remains endemic worldwide and is an important public health problem, even in countries with sustained high vaccination coverage. Resurgence of pertussis in the post-vaccination era has been reported in many areas of the world. The Global Pertussis Initiative (GPI) was established in 2001 to evaluate the ongoing problem of pertussis worldwide and to recommend appropriate pertussis control strategies. In addition to primary vaccinations, the GPI currently recommends a pertussis booster vaccination to pre-school children, adolescents and those adults at risk of transmitting Bordetella pertussis infection to infants. At a meeting in Paris, France, in January 2010, GPI members discussed pertussis surveillance and testing then prepared recommendations on the implementation and utilisation of these activities. Issues and projects discussed included: national surveillance systems and their suitability for other countries; seroprevalence studies; ideal surveillance methodologies; ongoing efforts in obtaining biological samples; standardisation of sample treatment; culture; real-time polymerase chain reaction (PCR); and likely future advances such as antibody detection in saliva. Previous regional meetings of the GPI have confirmed that many countries have limited laboratory facilities for the detection of pertussis. The GPI hopes that the future introduction of increased laboratory capabilities and greater harmonisation of clinical definitions and detection methods will lead to enhanced surveillance and a better estimate of the burden of pertussis infection worldwide. This article provides a current guide on the appropriate use of laboratory diagnostics and optimal surveillance methodologies to assist countries in the control of pertussis disease.

Introduction

The Global Pertussis Initiative (GPI) is an expert scientific forum, consisting of 35 global opinion leaders. The group has previously developed and published specific recommendations for vaccinations beyond childhood to limit the impact of the disease [1], [2], [3].

This paper describes the proceedings of the Round Table Meeting held in Paris, France, on 11–12 January 2010. The meeting aimed to discuss how pertussis was detected around the world, and how improvements could be made in diagnosis in order to gain a more accurate understanding of pertussis epidemiology in all age groups.

Infection with Bordetella pertussis results in whooping cough, characterised by a paroxysmal, convulsive cough that lasts several weeks. Infection can cause mortality among neonates and infants who are not immunised [4]. Pertussis infection also causes respiratory disease in adolescents and adults [5], [6], which can in turn be a major source of infection for vulnerable groups such as infants and the elderly [7], [8], [9], [10].

Over the past few years, there has been a resurgence of reported pertussis cases in many regions of the world where the vaccination coverage in young children is high. Reasons for this include (i) improved methods to detect infection; (ii) the waning of vaccine immunity (immunity to pertussis disease or vaccination is not lifelong); and (iii) a resultant increase in transmission of infection to infants from adolescents and adults [11], [12]. In addition, there has been debate in the literature that B. pertussis adaptation to vaccine induced immunity may be a possible cause of pertussis [13], [14], [15], [16].

Pertussis is often misdiagnosed beyond infancy, as it is not generally thought of as a disease that affects adolescent and adult populations, and adults rarely exhibit classical symptoms. However, the most rapid increase in the incidence of pertussis has been in these older age groups [5]. In 1999, a study in the United States showed that approximately 10% of reported cases were in people aged 15 years and older [5]. Similar trends have been reported elsewhere [17], [18], [19], [20], [21], [22], [23], [24].

Adults can have various degrees of symptomatic pertussis infection. Under-reporting in adolescents and adults occurs because patients will often present for medical treatment late in infection, when identification by culture is unlikely to be positive [5], [6], [25], [26].

Surveillance systems operate in many countries around the world to monitor B. pertussis disease and to determine the effectiveness of national control strategies (Table 1). However, there have been wide variations in the reporting of B. pertussis globally. Reasons for these differences include differences in the clinical criteria used for diagnosis, the methods of diagnosis (polymerase chain reaction [PCR], culture or serology), and differences in the surveillance systems used [12], [26].

Below is a description of the different national surveillance systems used in various countries and the vaccine strategies in those countries.

In Canada, pertussis is a notifiable disease in all provinces and all confirmed cases are reported nationally. Canada has two systems for reporting and confirming pertussis cases: a passive system, the Notifiable Disease Surveillance System (NDSS), and an active system: Immunization Monitoring Program, ACTive (IMPACT).

The NDSS is a national surveillance system with mandatory reporting and standardised case definitions. The limitations of this system include passive reporting, underreporting by clinicians, particularly in adolescents and adults, and low sensitivity of diagnostic testing.

IMPACT is a central government-funded surveillance system managed by the Canadian Paediatric Society. It was established in 1991 and involves 12 paediatric hospitals that represent approximately 90% of all tertiary care paediatric beds in Canada. It covers 50% of the Canadian paediatric population and has an annual admission rate of 75,000 patients (from 0 to 16 years old). Cases are difficult to detect in older children, adolescents and adults because IMPACT is hospital based and adults are usually only identified as contacts of paediatric cases.

Cases of pertussis in Canada are confirmed by culture isolation, PCR or epidemiological linkage with clinical symptoms. Probable and suspected cases of pertussis are defined clinically in the absence of laboratory confirmation, but these are not reported nationally. Previously, laboratory diagnosis of pertussis by PCR alone was enough to define a case as “confirmed.” This may have led to a “pseudo” outbreak in the Toronto area and now the presence of clinical symptoms is required for a confirmed case (S. Halperin, GPI meeting, January 2010).

The vaccine strategy in Canada consists of a primary vaccination series at 2, 4, and 6 months, an 18 month booster, a 4–6 year booster, and an adolescent booster at 12–16 years.

There is no mandatory notification system in France. Monitoring pertussis is performed by various sentinel systems: Renacoq is a paediatric hospital sentinel surveillance system that includes 43 hospitals and has been operational since 1996. Laboratory confirmation of cases occurs by culture and PCR along with some serology (measurement of anti-pertussis toxin antibodies by the reference ELISA technique) [23], [24]. The Sentinelle surveillance study carried out in Paris from May 2008 to March 2009 aimed to estimate the incidence of pertussis in the adult population [27].

Sentinelle reported a pertussis incidence rate of 145 cases per 100,000 adults. Most patients were female (66.2%) but this was attributed to the fact that more women than men visit physicians. The median age of the patients was 44 years and the median duration of cough at the inclusion date was 24 days [27].

In France the vaccination schedule consists of a primary vaccination series at 2, 3, and 4 months and a booster at 16–18 months. In 1998, an adolescent booster vaccine was introduced in France, following evidence that infants were being infected via adults and adolescents [7], [28].

Subsequent recommendations in 2004 encouraged the use of a third booster for adults planning to have children (cocoon strategy) and for medical and health staff in contact with children under 6 months old [24], [29]. These strategies have so far failed to achieve a greater proportion of immunisation of adults.

Current recommendations suggest a booster for people who have not received one within 10 years, for people planning on becoming future parents, for healthcare workers (including those working with the elderly), and for those people in contact with infants [23], [24], [30], [31].

There is no mandatory notification of pertussis in Germany. However, in former East Germany, there was mandatory reporting of pertussis, with reporting continuing after reunification [20]. In former West Germany, little is known of pertussis incidence, as notification of the disease has not been required since 1962.

Sentinel-based incidence estimation of adult pertussis was carried out in two cities of similar population size, one in the former East, and the other in the former West Germany, producing similar estimates of overall incidence [32].

Surveillance data for January 2002 to December 2007 reported that 93.8% of pertussis cases were laboratory confirmed; 1.9% had an epidemiological link to another laboratory-confirmed case and 4.4% were identified by clinical signs only [20]. The laboratory-confirmed cases were diagnosed by single high titer serology (56.2%), an increase in pertussis antibodies (26.9%), PCR (9.8%) and culture (1%). Private laboratories mainly provide confirmation of suspected pertussis cases.

Most cases of pertussis in Germany occur in late childhood and adolescence, with some additional cases reported in adults. A pre-school booster vaccine was introduced in Saxony in 2002, and because it reduced cases in late childhood it was made available across Germany [20]. In addition, adolescent boosters (9–17 years old) and an adult booster with Tdap are also recommended.

In the Netherlands pertussis became a notifiable disease in 1976, and disease cases are also recorded on a National Medical Register for hospitalisations and a death register [33]. Biological diagnoses (culture, PCR and serology) are available, with the cost of laboratory testing covered by the social security system. The Centre for Infectious Disease Control of the National Institute for Public Health and the Environment coordinates the National Immunization Programme and the serological diagnostic database. Large serosurveys were carried out in 1995–1996 and 2006–2007.

Since 1999, the vaccination schedule has included a dose at 2, 3, 4 and 11 months old. In October 2001, a booster at 4 years was introduced [34] and acellular vaccines have been used since 2005 [33]. Coverage in infancy is 96%, with pre-school booster coverage at 93% [33]. The introduction of the pre-school booster for 4-year-olds altered the epidemiology of pertussis, with a reduction of 45% in the disease burden in the targeted group [33], [35]. The median age of infection also changed from 5 years in 2001 to 11 years in 2008 [33]. Over the same period, there has been increasing incidence of pertussis in adolescents and adults. In The Netherlands, pertussis is still endemic with cyclic epidemics that occur every 2–3 years.

The national reporting system in Sweden is highly rated, with a comprehensive pertussis dataset collected over the past two decades. Notification of suspected pertussis cases is a legal requirement and the cost of laboratory surveillance is covered by the state.

Vaccination against B. pertussis was not available between 1979 and 1995. In January 1996, vaccination was re-introduced after three large efficacy studies in Sweden [36], [37], [38], [39], [40]. After the new acellular pertussis vaccines were introduced, all families with a child with laboratory-confirmed pertussis born since January 1996 were interviewed by telephone and all pertussis vaccinations and complications were described in yearly reports since October 1997 [41]. There has been a decrease in pertussis from 89–150/100,000 before the introduction of acellular pertussis vaccine to <10/100,000 in fully vaccinated cohorts after 1996, but this increase is least marked in under 1-year-olds. In long-term monitoring of childhood cohorts, evidence of waning immunity [40] has been shown after the age of 5–7 years [40], [41]. Booster vaccine at 5–6 years of age was therefore introduced in children born from 2002 onwards, and a decrease of pertussis after booster dosage has recently been shown [42]. Furthermore, a “school-leaving” booster dose will be introduced for adolescents at 14–16 years of age.

Notification of pertussis is not required. Data for pertussis are thus collected by a sentinel-based system. The Swiss surveillance system, SENTINELLA, was established in 1991 and involves the participation of approximately 200 GPs, paediatricians and internists in private practice. Suspected cases are reported by clinical criteria with cases confirmed by PCR.

From July 1991 to December 2006, there were 4992 reported pertussis cases. Since 1994, approximately 80% of all reported cases were tested using PCR, 24% of which were positive. Overall, there is likely to be a high level of under-reporting in Switzerland, as PCR is only likely to be used when clinical symptoms suggest a pertussis infection. The last major pertussis epidemic in Switzerland occurred in 1994. Since 2000, there has been a shift in the age of patients infected with pertussis. Most pertussis infections were observed in those aged between 6 and 20 years, with an increase in adult cases.

In Switzerland, there is a primary vaccination at 2, 4 and 6 months. In 1995, a fourth and fifth dose was added to the schedule for patients aged 15–24 months and 4–7 years. At this time, there is no recommendation for adult vaccination (U Heininger, GPI meeting, January 2010).

Pertussis is a notifiable disease in all US states. In addition, increased serosurveillance in the United States is carried out in three sentinel states: Massachusetts (the longest established), Minnesota and Oregon. All have funded and centralised diagnostic facilities with well-characterised tests.

Since 1993, clinical cases of pertussis in Massachusetts have been defined according to the Centers for Disease Control and Prevention (CDC) criteria. A clinical diagnosis is made if the patient has a cough that lasts for 2 weeks or more and has one of the following: paroxysms of coughing, inspiratory whoop or post-tussive vomiting [43].

Laboratory criteria for diagnosis are divided into the following:

  • Bacteriological cases: isolation of B. pertussis from a clinical specimen or positive PCR, regardless of clinical symptoms.

  • Serologic cases: for people 11 years and older, a positive single serum anti-pertussis toxin (PT) antibody level is required and the person has to meet the clinical case definition for pertussis.

  • Epidemiologically linked cases: occurs in a person with clinical symptoms (fulfils the clinical case definition) and the person has had contact with a laboratory confirmed case [43].

Recently, there has been a rise in reported cases of pertussis, but this is likely due to an increase in testing. The number of positive cases has remained the same even though there has been an increase in the number of samples sent for analysis.

The Massachusetts Department of Public Health has extensive and intensive pertussis surveillance. Free diagnostic testing for pertussis is provided, including culture and serodiagnosis. Since 1987, a single serum PT antibody assay for people 11 years and older has been used, standardised with serum provided by the US Food and Drug Administration (FDA). The specificity of the assay is 99%, with a 99% upper tolerance limit [44]. For those with a cough lasting 2 weeks or more, the assay is 67% sensitive (95% confidence interval [CI]: 53–81%) but it is 36% sensitive (95% CI: 20–52%) for a person with a cough lasting less than 2 weeks [44]. Thus this test has a high predictive value when positive but is poor at excluding pertussis when negative. Although serological methods are more sensitive than diagnostic culture methods, care must be taken when establishing serologic cut-offs [25], [44]. Massachusetts set a high cut-off, with high specificity, to confirm that they are reporting real disease, although they will miss some cases. If the cut-off is set lower, more disease will be detected, but more false positive cases will also be reported. In the future, the Massachusetts model may be used in other states.

In the United States, the vaccine strategy consists of a primary vaccination at 2, 4, and 6 months, a booster at 15–18 months and second booster at 4–6 years. In 2005, the US FDA licensed two vaccines, one for use in adolescents and the other for use in adolescents and adults [45]. Since the introduction of the adolescent booster, the number of cases in this group has been decreasing (Marchant, personal communication). The adolescent Tdap booster vaccine effectiveness has been reported as 65.6% (95% CI: 35.8–91.3%) [46].

Ideally, surveillance systems would be standardised globally. There would be a clear clinical case definition for the disease, including in older age groups. Diagnostic protocols would be standardised, including those for sample collection, PCR, culture and serology. Fortunately, such advances are being made in these areas.

Sweden and the Netherlands may be examples of countries with a well-executed surveillance system. Sweden is able to follow total birth cohorts, allowing the collection of complete data sets for children. In addition to notification, the Netherlands use seroprevalence studies to investigate adult cases of pertussis and the spread of the disease to infants. In an ideal world, all countries would follow Sweden's or the Netherlands’ example of following total birth cohorts, but this is expensive and is not needed worldwide as it is likely that similar disease characteristics would be detected. In the United States, a different system is used where, in addition to formal notification, three sentinel states with increased surveillance are used to gain an understanding of the disease in the country as a whole. The specificity and sensitivity of the surveillance assays to pertussis are not formally known, but the surveillance is sufficient for trends and burden of pertussis disease in different age groups to be determined. This approach is probably the most cost-effective solution and one that many countries could use to improve their surveillance.

A paediatric hospital-based surveillance network, as shown in France since 1996, is useful to monitor the trend of pertussis among children and the impact of vaccination strategies. Data derived from the network [24], in addition to studies in the adult population [27], [47] and transmission studies [7], [9], supported the introduction of adolescent and adult boosters.

Currently, the duration of vaccine immunity is not known, which provides a hurdle to designing the best strategy to combat pertussis. A study is ongoing in France [48] to determine the length of vaccine-induced immunity.

Section snippets

Sampling methodology

The timing of sample collection is crucial. If the sample is collected near the beginning of infection (up to 3 weeks of cough), PCR is the most sensitive test available [12]. Culture also requires samples taken early in infection. Often patients, particularly adults, present late in infection, when PCR and culture can often give false-negative results. Serology is more useful at late times of infection (after 3 weeks of cough) [12].

Nasopharyngeal aspirates should be taken correctly, from the

Conclusions

There is a need to raise awareness of pertussis to enhance clinical recognition and diagnosis of infection in adolescents and adults, as well as children. More accurate studies to determine incidence, transmission, and disease burden will help in this regard. Education of healthcare workers and the general public, highlighting the existence of infection in all age groups, would help to control and minimise the spread of pertussis. In addition, improved clinical diagnosis with standardised PCR

Acknowledgements

Dr Guiso has received research grants from sanofi pasteur and GSK and she has done speaking and teaching for both companies. Dr Wirsing von König has received unrestricted research grants from sanofi pasteur and GSK, and he has given talks for sanofi pasteur and GSK. Dr Tan has received unrestricted research grants from sanofi pasteur and Merck; she has done speaking and teaching and has served on advisory committees for sanofi pasteur, Merck, and Wyeth; she serves as a consultant for sanofi

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    The meeting attendees were the following: Guy Berbers, James Cherry, Thomas Clark, Michael Decker, Kevin Forsyth, Norman Fry, Anna Giammanco, Sabine de Greeff, Nicole Guiso, Scott Halperin, Ulrich Heininger, Daniela Hozbor, Colin Marchant, Lennart Nilsson, Stanley Plotkin, Marion Riffelmann, Tina Tan, Usa Thisyakorn and Carl Heinz Wirsing von König.

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