Reemergence of Pertussis in the Highly Vaccinated Population of The Netherlands: Observations on Surveillance Data

Hester E. de Melker, J.F.P. Schellekens, S.E. Neppelenbroek, F.R. Mooi, H.C. Rümke, M.A.E. Conyn-van Spaendonck, National Institute of Public Health and the Environment, Bilthoven, the Netherlands

Disclosures

Emerging Infectious Diseases. 2000;6(4) 

In This Article

Methods

Case Reporting. Data from pertussis reporting (required by law since 1976) were obtained from 1976 to 1998 from the Inspectorate of Health. A case definition, introduced in 1988, included clinical symptoms and laboratory confirmation (or close contact with a person with laboratory-confirmed pertussis). The clinical symptoms are a serious cough >2 weeks, coughing attacks, or coughing followed by vomiting and at least one of the following: apnea, cyanosis, characteristic cough with whooping, subconjunctival bleeding, or leukocytosis. From 1988 to April 1997, laboratory confirmation was defined as either a positive culture of B. pertussis (or B. parapertussis) or positive two-point serology, in turn defined as a significant rise of immunoglobulin (Ig) G antibodies against pertussis toxin or IgA antibodies against B. pertussis in paired sera. In April 1997, a positive polymerase chain reaction (PCR) and positive one-point serology were also accepted as laboratory confirmation. Positive one-point serology was defined as high IgG or IgA antibody titers in a single serum sample.

From 1976 to 1988, only aggregated data were available on the total number of patients per year. These data included case-reporting date, number of vaccinated (at least three vaccinations) and unvaccinated or incompletely vaccinated patients, and number of patients with unknown vaccination status, with age at the time of report, by age-group (<1, 1-4, 5-9, and >= 10 years). From 1989 to 1992, the age (in years) and date of reporting were available for individual patients, while the aggregated data on vaccination status were similar to those of 1976 to 1988. Since 1993, the date of onset of symptoms, date of birth, age in years at the time of reporting, vaccination status, method of laboratory diagnosis, and contact with a person with laboratory-confirmed pertussis were included in the database. The method of laboratory diagnosis was differentiated as "microbiologic" (positive culture or PCR), "serologic," "epidemiologic" (i.e., contact with a patient with laboratory-confirmed pertussis), and "unknown."

The case distribution from 1976 to 1988 could only be assessed by date of reporting. From 1989 to 1992, the date of onset of symptoms was estimated by finding the median duration between date of first symptoms and date of reporting (1993 to 1994). This median duration (81 days) was then subtracted from the reporting date of the case at hand. The distribution of cases in 1989 to 1992 was based on this estimate, and age distribution was based on age at the time of reporting. For 1993 to September 1998, the distribution of cases was based on the date of first symptoms available in the database, and the age distribution was based on age at onset of symptoms.

Hospitalizations and Deaths. The number of hospitalizations with pertussis as the main diagnosis (ICD-9-CM 033) in 1976 to 1997 was obtained from the registry of the Foundation Information Center for Health Care. For 1989 to 1997, data were available by age-group (<1, 1-4, 5-9, 10-14, 15-19, 20 years).

The number of deaths (by age, in 5-year increments) caused by pertussis in 1976 to 1997 was obtained from the Central Bureau of Statistics.

Serology. Data on pertussis serology were obtained from the National Institute of Public Health and the Environment, the only laboratory in the Netherlands that performed serologic tests for suspected-pertussis patients from 1982 through January l, 1998. Other laboratories have performed an estimated 10% to 15% of serologic tests since 1998.

Serologic testing consisted of measuring IgA antibodies against a crude cell-wall preparation of B. pertussis (available since 1981) and IgG antibodies against purified pertussis toxin (available since 1984) in enzyme-linked immunosorbent assays, according to described methods that have not changed over time[10,11]. The potency of the used reference sera was stable. Serologic interpretations have varied over the years. In 1982 to 1988, mostly single serum specimens were submitted. Since vaccination with the Dutch whole-cell vaccine only induces low levels of IgG against pertussis toxin (IgG-PT) and no IgA against B. pertussis (IgA-Bp), detection of IgA-Bp (sonicated mixture of the two strains included in the Dutch whole-cell vaccine) or moderate, high, or very high IgG-PT was reported as supportive of pertussis.

By 1987, it became clear that low and moderate IgG-PT and IgA-Bp levels were present in a large proportion of the population and that the prevalence increased with age. Therefore, in 1988, serologic interpretation of single serum specimens was abandoned, and only significant increase of IgG-PT or IgA-Bp in paired sera was considered confirmation of pertussis. The same year, a strict case definition for pertussis reporting was introduced, which included "positive two-point serology" in the laboratory-confirmation criteria. However, in 1993, when serum specimens from the population, vaccinees, and pertussis patients were tested, high IgG-PT or high IgA-Bp levels (greater than an age-specific cut-off value) were found to be very rare in the population (<2.5%). Such levels were not induced by vaccination, were present in at least 90% of patients with PCR- or culture-confirmed pertussis, and decreased again within 6 months to levels below the cut-off value[12,13,14]. Since 1994, the laboratory-reported detection of such high values in one or both samples of a serum pair indicates "possible pertussis," although the case definition for reporting remained unchanged. From April 1997, the detection of such high levels in patients' samples was formally defined as "positive one-point serology" and was included in the case definition for reporting as laboratory-confirmed pertussis.

From the serologic database, we retrieved data on patients whose date of disease onset was January 1989 to September 1998 and for patients whose date of serologic result was January 1986 to December 1987. Patients with positive two-point serology in 1989 to 1998 and patients with positive one-point serology in 1994 to 1998 were selected. The criteria we recently defined for positive one-point serology were retrospectively applied to the serologic data of 1986-1987 and 1989-1993. The distribution of cases in 1986 and 1987 was calculated based on the year of the test result and, in 1989-1998, based on the year of first symptoms.

We used Epi-Info version 6.04 to estimate vaccine effectiveness1 in persons ages 1 to 4 and 5 to 9 years (reporting data from 1976 to 1997), assuming an average vaccine coverage in the Dutch population of 96%. We compared completely vaccinated persons (at least three vaccinations) with incompletely vaccinated or unvaccinated persons[15].

Since positive serologic results are included in the case definition for reporting, the serodiagnosis and reported-case databases are not independent sources. For 1993 to 1997, the reported-case database and the database with records of serodiagnosis were linked at the individual-patient level to verify the type of serodiagnosis (positive two-point or positive one-point serology) on which the reporting was based. The completeness of the reported-case database was calculated from the proportions of reported patients with positive two-point and one-point serologic results. We used the statistical package SAS to analyze the data.

1 Vaccine effectiveness = 1 - (proportion of vaccinated cases/1 - proportion of vaccinated cases) X (1 - proportion vaccinated in the population/proportiion vaccinated in the population).

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