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Resurgence of Pertussis in Europe

Celentano, Lucia Pastore MD, MSc*†; Massari, Marco DStat*; Paramatti, Daniele DStat; Salmaso, Stefania DBiol*; Tozzi, Alberto Eugenio MD§ on Behalf of the EUVAC-NET Group

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The Pediatric Infectious Disease Journal: September 2005 - Volume 24 - Issue 9 - p 761-765
doi: 10.1097/01.inf.0000177282.53500.77
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Abstract

Nearly 20–40 million cases of pertussis occur every year worldwide, with 200,000–400,000 deaths. Although pertussis may occur at any age, most severe cases and the majority of fatalities are observed in early infancy.1,2

The introduction of universal pertussis immunization and the high coverage achieved in most developed countries have largely changed the epidemiology of the disease. After the introduction of the vaccine and a subsequent substantial decrease in incidence, a resurgence of pertussis has been observed in many countries, particularly in infants and adults. Such an increase in incidence has been reported in Canada from 1990,3,4 in the United States where pertussis incidence increased since the 1980s5–8 and in Australia since 1992.9

In Europe, a resurgence of pertussis has not been consistently documented thus far. Although decreasing trends have been observed in England and Wales, Ireland, Sweden and Spain,10–13 large outbreaks occurred in the Netherlands and Switzerland, and an increasing trend has been observed in Norway.14–20 Moreover a sustained circulation of Bordetella pertussis infections has been observed in children and adults in France despite a long history of vaccination.21,22

In 1998, the European Parliament and Council decided to set up a network for the epidemiologic surveillance and control of communicable diseases in the European Community and funded a project to start a surveillance community network for measles and pertussis, the EUVAC-NET project.23 This paper describes the epidemiology of pertussis in 16 European countries in the years 1998–2002.

MATERIALS AND METHODS

Data Sources.

Data from routine or sentinel national surveillance systems were used for the analysis of data. The information gathered for each pertussis case included age, sex, date of onset of symptoms of pertussis, vaccination status, hospitalization and outcome (survival or death).

Case Definitions.

The recommended WHO case definition for pertussis24 was not used in all participating countries. Those that diverged from WHO case definition included: France, which used 3 weeks of cough or 1 week of typical cough; and Iceland, Ireland, Italy and Malta, which provided notifications based on the clinical diagnosis by the physician only. Eight countries (Austria, France, Germany, Greece, the Netherlands, Norway, Portugal, England, Wales and Northern Ireland) included serology for laboratory confirmation of cases, and 6 (Denmark, France, the Netherlands, Portugal, Sweden, Switzerland) included polymerase chain reaction.

For the purpose of this study, all cases meeting the requirements for national surveillance, either clinical or laboratory-confirmed, were included in the analysis.

A vaccinated person was defined as an individual who received at least 1 dose of vaccine, therefore including partially immunized individuals.

National Surveillance Systems.

All countries have a surveillance system that collects case-based information, except Austria, which provided aggregated data. Most surveillance systems cover the general population. However, in Denmark, cases are reported only if children were 24 months old or younger, and France and Switzerland provided data from a sentinel surveillance system. Moreover Germany reported cases observed in Federal East Germany only (5 of 16 Federal States) and England, Wales and Northern Ireland reported data from a laboratory-based surveillance system.

Data Analysis.

Incidence rates by country and age group, hospitalization and case fatality rates were calculated. Denominators used for calculating incidence rates were derived from The Computerized Information System for Infectious Diseases of the Regional Office for Europe of the World Health Organization25 or from local census data.

A reference population was not available for France where the system is based on hospital admissions, and its data were not used for calculating incidence figures.

The following age groups were considered for the analysis: infants younger than 1 year; children 1–4 years old; children 5–9 years old; children 10–14 years old; and persons older than 14 years. Because Denmark provided data on cases 0–2 years of age only; its data were included only in the calculation of incidence in infants younger than 1 year.

Trends of incidence by age group over time were calculated pooling only data from countries for which the information was complete on the entire period 1998–2002. Pooled hospitalization proportions and case fatality rates were calculated as well for countries that provided this information.

Seasonality was studied examining the distribution of all cases by month of onset of the disease. Adjusted risk ratios and 95% confidence intervals for hospitalization by number of vaccine doses received and age group were estimated with a multivariate Poisson regression model with robust variance estimation26 including children 2–12 months. Microsoft Access 2000 (Microsoft, Redmond, WA) and the SPSS statistical package (version 11.0; SPSS, Chicago, IL) were used for the analysis.

RESULTS

Incidence.

In 1998–2002, the 16 participating countries reported a total of 79,217 cases of pertussis. The majority of cases (89%) was provided by only 5 of 16 countries, namely the Netherlands, Italy, Norway, Sweden and Germany. The overall male-to-female ratio was 83:100.

Incidence varied widely by country. The highest figures were reported in most Northern European countries, especially in Switzerland, Norway, the Netherlands and Sweden, whereas the incidence of pertussis in the other countries was ≤10 per 100,000 (Table 1).

T1-3
TABLE 1:
Mean Annual Number of Pertussis Cases per 100,000 Population by Country and Age Group, 1998–2002

Several countries reported the highest incidence in the younger than 1 year age group. The highest values were observed in Switzerland and Denmark, whereas Norway, Iceland, the Netherlands and Italy reported an incidence of >100 per 100,000.

Incidence was highest in the 1- to 4-year age group in the Netherlands, in the 5- to 9-year age group in Sweden and Malta and in the 10- to 14-year age group in Germany and Norway.

In France, where incidence was not calculated, 69% of cases were reported among infants younger than 1 year and 3% in persons older than 14 years.

Figure 1 illustrates the cumulative incidence by age group and calendar year in the period 1998–2002 only for countries providing a complete data set in the period under study.

F1-3
FIGURE 1.:
Number of pertussis cases per 100,000 population by age-group and year. Incidences are plotted on a logarithmic scale. The graph includes data from Germany, Greece, Iceland, Italy, Malta, Norway, Portugal, the Netherlands and England, Wales and Northern Ireland.

The global incidence remained stable over time. Infants younger than 1 year experienced a decrease in incidence from 1998 to 2001 and then remained stable. Incidence rates in children 1–4 and 5–9 years decreased over time, were stable in persons 10–14 years old and increased by 115% from 1998 to 2002 in individuals older than 14 years.

The median age of cases increased from 7 years in 1998 to 11 years in 2002. The change in age distribution was a result of a decrease in the relative proportion of cases in the 5- to 9-year group (36% of cases in 1998 and 23% in 2002) and of an increase in the relative proportion of cases in persons older than 14 years (16% in 1998; 35% in 2002).

Seventy-one percent of cases were laboratory-confirmed; however, this proportion increased with age, being 59.4% in children younger than 1 year and 91.7% in persons older than 14-year-old. The proportion of laboratory-confirmed cases was 58.9% in unvaccinated compared with 81.5% in vaccinated patients.

Seasonality.

Twenty-eight percent of cases occurred in the July–September period. However, no seasonal pattern was apparent when evaluating all data combined. A simultaneous peak in the summer period was evident only in infants younger than 1 year of age and in children 1–4 years. A modest peak in May was observed in the 10- to 14-year age group. In all the other age groups, there was no evidence of any seasonal pattern (Fig. 2).

F2-3
FIGURE 2.:
Proportion of pertussis cases by age group and month of onset, 1998–2002.
Hospitalization.

The proportion of hospitalized cases decreased with age: 70.1% in younger than 1 year; 13.6% in children 1–4 years; 6.3% in those 5–9 years; <4% in children 10–14 years of age; and 2.5% in persons older than 14 years. The effect of vaccination and age at the time of hospitalization is shown in Table 2. Infants 2–6 months were more likely to be hospitalized than those 6–12 months of age independently from vaccination. Vaccination protected from hospitalization with an increasing effect with the number of doses independently from patient age.

T2-3
TABLE 2:
Effect of Age and Number of Doses of Pertussis Vaccine on Hospitalization
Deaths and Case Fatality Rate.

A total of 32 deaths were reported in the 5-year period. All deaths occurred in the first year of life with the exception of 1 case in the 5- to 9-year age group and 1 case in the older than 14-year age group. The case fatality rate per year in infants younger than 1 year was 6.3 per 1000. Four of the 11 countries that declared to collect information on death (Greece, Iceland, Malta and Switzerland) did not report any fatal case during the study.

Most deaths occurred in infants too young to be vaccinated, particularly those younger than 6 month of age (Table 3). Among the 28 children younger than 6 months of age, 17 (53%) were younger than 2 months old. One death occurred in a 9-year-old child who received 4 vaccine doses, and 1 occurred in an adult with unknown vaccination status. Events reported from England, Wales and Northern Ireland and France accounted for 26 of the 32 deaths.

T3-3
TABLE 3:
Characteristics of the 32 Deceased Notified Patients in 16 European Countries, 1998–2002

DISCUSSION

This is the first appraisal of the epidemiology of pertussis in Western Europe. This study attempted to reconcile data from countries with universal and sentinel surveillance systems, different case definitions and different vaccination backgrounds. Although the heterogeneity of surveillance systems may have selected severe cases and may have failed to detect cases among adolescents and adults who present with aspecific symptoms, the results offer the opportunity for examining the trend of disease over time, assessing the impact of control programs and for considering new vaccination strategies.

The incidence reported by individual countries varied widely. This result may depend on a real difference in the magnitude of incidences, by a differential sensitivity of surveillance systems or by a combination of both factors.

According to notified data, pertussis seems more frequent in Northern European countries where the highest figures were observed mainly in children older than 4 years. This observation may be explained by the accumulation of older susceptible children in some countries such as Sweden and Germany that achieved a high immunization coverage only recently27 and by the absence of a booster dose after primary immunization at the time the study was conducted in some countries such as Germany, Norway, Sweden and the Netherlands.28

In the remaining countries, the highest incidence was observed in infants younger than 1 year of age. The incidence trend in infants younger than 1 year of age showed a progressive decrease and a stabilization in the last 2 years of the study, whereas incidence steadily decreased in children 1–9 years. This effect may be caused by a progressive increase in vaccination coverage in some countries.

The incidence in persons older than 14 years doubled in the study period, and the median age of cases increased significantly with time. Adolescents and adults represent therefore an increasing reservoir of pertussis in Western Europe but may be often unrecognized because they carry the least specific symptoms when affected by the disease.29 The observed increase in adolescents and adults might be caused by waning immunity in immunized persons. In fact, the immunity induced by immunization is shorter than after the natural disease,30 and this might explain why pertussis is reemerging in adolescents and adults in countries with a long history of high vaccination coverage.8,22 It is likely that the progressive increase in vaccination coverage and the decrease in frequency of natural boosters will determine more cases in adolescents and adults in Europe.

A high case-fatality rate in the first year of life has been observed in our study. As observed in other countries,31 the majority of deceased patients were too young to be vaccinated, although some of these patients did receive immunization. This finding suggests that pertussis may also be severe in vaccinated children, especially in the first year of life.

The lack of reports of pertussis deaths by some countries with moderate or high incidence suggests that some surveillance systems are not appropriate to detect these events and should be integrated with information from death registries. Because there is no plausible reason to observe different grades of severity of pertussis in different countries, we also speculate that most severe cases occurring in the first 6 months of life might go unreported or misdiagnosed by routine surveillance as already suggested.32

In this respect, despite the fact that >70% of pertussis cases were laboratory-confirmed in this study, the surveillance methods used varied widely among participating countries, and some of them still rely on clinical diagnosis only.28 A standardization of laboratory diagnostic methods is therefore a priority in Europe.

The trends of pertussis in Europe differ from those reported in the United States. An increasing incidence in infants and in adults has been observed since the 1990s in the United States.8,33,34 In Europe, pertussis incidence is still high in infants younger than 1 year, an increasing trend has not yet been observed in this age group and the increase in adults has probably started recently.

A typical summer peak of pertussis cases was observed only in children younger than 5 years. In the United States, a similar recent analysis showed a summer peak in infants and young adults.8 This finding supported a role of transmission by older patients to infants because of waning immunity or because they were too old to have received immunization. The common seasonality in children 0–4 years old and the lack of summer peaks in older age groups in Europe support an important role of contacts among children in transmission of pertussis.

Our data support a protective role of vaccination on hospitalization starting from the first dose as shown in other studies.35,36 Because several European countries start pertussis immunization at 3 months of age27,28 appropriate recommendations should be reinforced to favor the initiation of immunization as soon as 6 weeks of age. Moreover all European countries might consider introducing a booster dose in preschool age and at least in adolescents as recently implemented in several countries.29 To overcome waning immunity, a booster dose of pertussis vaccine every 10 years in adult age is a reasonable although expensive strategy to limit the circulation of the disease. The burden of pertussis described in this paper is high. The number of cases, hospitalizations and deaths makes this disease a priority in planning future prevention strategies in Europe.

ACKNOWLEDGMENTS

We acknowledge the work of Steffen Offersen Glismann (Staten Serum Institut, Copenhagen, Denmark), who participated in the coordination of the EUVAC-NET project; and Alain Moren (European Programme for Intervention Epidemiology Training, EPIET) and Usha Gungabissoon (Health Protection Agency, Communicable Disease Surveillance Centre, London, UK), for their useful suggestions during the preparation of the manuscript.

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APPENDIX

The members of the EUVAC-NET group: Austria: Reinhild Strauss; Denmark: Peter H. S. Andersen; France: Bonmarin Isabelle; Germany: Anette Siedler; Greece: Takis Panagiotopoulos; Iceland: Gudrun Sigmundsdottir; Ireland: Suzanne Cotter; Italy: Loredana Vellucci; Malta: Andrew Amato-Gauci; the Netherlands: Sabine de Greeff; Norway: Oistein Lovoll; Portugal: Teresa Fernandes; Spain: Carmen Amela; Sweden: Arneborn Malin; Switzerland: Mathieu Forster; England, Wales and Northern Ireland: Joanne White.

Keywords:

pertussis; epidemiology; Europe; surveillance

© 2005 Lippincott Williams & Wilkins, Inc.