Sensor, a Population-based Cohort Study on Gastroenteritis in the Netherlands: Incidence and Etiology

M. A. S. de Wit1, M. P. G. Koopmans2, L. M. Kortbeek3, W. J. B. Wannet3, J. Vinjé2, F. van Leusden4, A. I. M. Bartelds5 and Y. T. H. P. van Duynhoven1

1 Department of Infectious Diseases Epidemiology, National Institute of Public Health and the Environment, Bilthoven, the Netherlands.
2 Research Laboratory for Infectious Diseases, National Institute of Public Health and the Environment, Bilthoven, the Netherlands.
3 Diagnostic Laboratory for Infectious Diseases and Perinatal Screening, National Institute of Public Health and the Environment, Bilthoven, the Netherlands.
4 Microbiological Laboratory for Health Protection, National Institute of Public Health and the Environment, Bilthoven, the Netherlands.
5 Netherlands Institute of Primary Health Care, Utrecht, the Netherlands.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 REFERENCES
 
A prospective population-based cohort study with a nested case-control study was conducted to estimate the incidence of gastroenteritis and the associated pathogens in the general Dutch population. Follow-up of two consecutive cohorts was performed by weekly reporting cards from December 1998 to December 1999. Cases and controls in the case-control study supplied a questionnaire and stool samples. The standardized gastroenteritis incidence was 283 per 1,000 person-years. The incidence rose with increasing level of education and was higher for persons with a history of diarrhea and for young children. Bacterial pathogens accounted for 5% of cases, bacterial toxins for 9%, parasites for 6%, and viral pathogens for 21%, with Norwalk-like virus (NLV) as the leading pathogen in 11% of cases. The gastroenteritis incidence was higher than that reported for England, but lower than for the United States. In community cases, viral pathogens are the leading cause of gastroenteritis, with NLV being the number one cause of illness in all age groups but one. In many countries, preventive measures are implemented to decrease bacterial infections. However, additional prevention of viral infections, especially NLV, might significantly decrease the number of gastroenteritis cases in the community.

Campylobacter; gastroenteritis; Giardia lamblia; Norwalk-like viruses, population-based; rotavirus; Salmonella; Sapporo-like viruses

Abbreviations: NLV, Norwalk-like virus; RT-PCR, reverse transcriptase-polymerase chain reaction; SLV, Sapporo-like virus.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 REFERENCES
 
Gastroenteritis is one of the most common diseases throughout the world (1Go, 2Go). In industrialized countries, such as the Netherlands, the associated mortality is low, but morbidity remains high. Most episodes of gastroenteritis are brief and do not require medical attention, but the social and economic burdens are substantial because of the high incidence. With a few exceptions (3GoGo–5Go), studies estimating the incidence and burden of disease of gastroenteritis focus on patients seen at some level of the health care system or at certain age groups. These patients are a minority and are a nonrandom selection of all patients. Little is known about health care-seeking behavior, but it is likely that the severity and duration of symptoms play a role. Because these factors are also related to the pathogen causing the symptoms, the relative importance of the various pathogens will differ between patients who seek medical advice and those who do not. To estimate the incidence and disease burden of gastroenteritis at the population level, to study the causative pathogens and the selection of patients consulting a general practitioner, and to identify transmission modes, two studies were performed. A population-based cohort study (Sensor) was performed in combination with a study among cases presenting to general practitioners (6Go, 7Go). This paper describes the population-based study estimating the incidence of gastroenteritis in the general population and the causative pathogens in different age groups.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 REFERENCES
 
Study design
The study was designed as a prospective, population-based cohort study with a nested case-control study. To include an entire year in the study, two consecutive cohorts of 6 months were included from December 14, 1998 to June 13, 1999 and from June 14 to December 13, 1999. An age-stratified random sample was drawn from all persons registered at the participating sentinel general practices from the Netherlands Institute of Primary Health Care (8Go). Of the 44 practices in the network, 27 practices participated in the first cohort and 31 in the second. The age groups used for stratification were 0, 1–4, 5–11, 12–64, and 65 years and older. The number of invited persons was based on an expected response rate of 35 percent and a power calculation for estimating age group-specific incidences with a precision of 10 percent and estimating the overall ratio of community versus consulting cases with a precision of 20 percent. Persons were invited by mail, and after 3 weeks, a reminder was sent to nonrespondents. The reply card included five questions for nonparticipants concerning the reason for nonparticipation, level of education, country of birth, and diarrhea or vomiting in the previous 2 months. All participants signed an informed consent. The study was approved by the Medical Ethical Committee of the Institute for Applied Scientific Research, TNO, Zeist, the Netherlands.

At the start of follow-up, all participants were asked to complete a baseline questionnaire. During follow-up, participants sent in a card weekly, reporting the presence or absence of gastrointestinal symptoms in the previous week. For weeks spent abroad, no reporting of symptoms was requested.

All participants were instructed at the beginning of the study to contact the study coordinator by telephone if they developed symptoms of diarrhea or vomiting. In addition, a stool sample had to be collected immediately. The study coordinator checked whether the case definition of gastroenteritis was met, i.e., at least three loose stools in 24 hours or vomiting at least three times in 24 hours or diarrhea with two or more additional symptoms or vomiting with two or more additional symptoms in 24 hours. The additional symptoms could be diarrhea, vomiting, abdominal cramps, abdominal pain, fever, nausea, blood in the stool, or mucus in the stool. If there was an obvious noninfectious cause, the case was excluded. If symptoms of diarrhea or vomiting were reported only on weekly cards, the participant was contacted by telephone. For each case, a control was invited from the cohort, matched on age, degree of urbanization, and region. Participants were invited as a control only once in the study period. After a case episode, a 2-week symptom-free period was taken into account before a participant could become a control or a case again. Cases and controls completed a questionnaire about risk factors and submitted stool samples (cases: four samples: days 0, 7, 14, and 21 after onset of disease; controls: days 0 and 7 after inclusion as a control). Cases also completed a medical diary for 4 weeks, reporting daily about gastrointestinal symptoms, bed rest, absence from work or school, use of medication, and use of the health care system.

Laboratory methods
Stool samples were sent by regular mail to the National Institute of Public Health and the Environment and consisted of a nonfixated sample and a sample fixated in sodium acetate, acetic acid, and formalin (1.6 percent) (9Go). Stool samples were tested for pathogenic bacteria, viruses, parasites, and bacterial toxins. The presence of pathogenic bacteria was assayed by routine culture assays on selective media, combined with polymerase chain reaction for detection of the Escherichia coli virulence-associated genes. Rotavirus group A, adenovirus type 40/41, and astrovirus were tested by enzyme-linked immunosorbent assay (7). Sapporo-like virus (SLV) and Norwalk-like virus (NLV) were assayed by a newly developed reverse transcriptase-polymerase chain reaction (RT-PCR) (10Go, 11Go). The presence of parasites was studied by microscopic examination of four different preparations of fixated samples. A more detailed description of these methods is given elsewhere (7Go). A random set of first samples of cases and controls were also tested for Bacillus cereus and other Bacillus species, for enterotoxins A, B, C, and D of Staphylococcus aureus, and for enterotoxin of Clostridium perfringens. The presence of enterotoxins of S. aureus and C. perfringens was assayed with a detection kit by reversed passive latex agglutination (SET-RPLA for the detection of staphylococcal enterotoxins A, B, C, and D in food samples or culture filtrates and PET-RPLA for the detection of C. perfringens enterotoxins in fecal samples or culture filtrates; Oxoid, Basingstoke, United Kingdom). A sample was considered positive for enterotoxin of S. aureus if any 1:10 (or higher) dilution with the latex sensitized with antienterotoxin A to D showed an agglutination as described by the manufacturer and the corresponding dilution with control latex did not show an agglutination. A sample was considered positive for enterotoxin of C. perfringens if any 1:10 (or higher) dilution with the latex sensitized with antienterotoxin showed an agglutination as described by the manufacturer, if the corresponding dilution with control latex did not show an agglutination, and if no inhibitive effect of a dilution series of the feces was shown on a known concentration of C. perfringens enterotoxin. B. cereus and Bacillus species were cultured on mannitol egg yolk polymixin agar according to International Organization for Standardization document 7932:1993. Specific colonies for B. cereus or Bacillus species were isolated and confirmed for B. cereus or Bacillus species by identification of fatty acid composition. A sample was considered positive for B. cereus or Bacillus species if a confirmed colony was isolated in 1:1000 dilution. All stool samples were stored for future investigations at 4°C and -70°C.

Statistical analyses
The representativeness of participants was estimated by a comparison with nonparticipants and with the Dutch population if data were available (12Go). The degree of urbanization was categorized by addresses per km2 as "very high" (>2,500), "high" (1,500–2,500), "moderate" (1,000–1,500), "low" (500–1,000), and "none" (<500). In the classification of degree of urbanization in the Netherlands Institute of Primary Health Care network, the categories high, moderate, and low were grouped as "urbanized." The highest educational level achieved by those aged 18 years and older and by one of the parents for those aged 0–17 years was classified as low (primary school, lower vocational or lower general secondary education), intermediate (intermediate vocational or intermediate general secondary and higher general secondary education), and high (higher vocational secondary education and university education). A multivariate logistic regression model was used to estimate the independent associations with response. A p value of 0.05 was considered statistically significant. Contribution to the model was based on the likelihood ratio parameter.

The total number of cases included participants in the case-control study and additional cases identified from weekly cards only. For the calculation of person-years at risk, weeks for which no weekly card was received, weeks abroad, and weeks included in a gastroenteritis episode or in the two symptom-free weeks afterwards were excluded. For extrapolation to the general population, the incidence was standardized by age, gender, and cohort according to the distribution in the Dutch population in 1999 (12Go). Poisson regression analyses were used to estimate the independent effects of demographic variables on the incidence. Age, gender, and cohort were included in the final multivariate model, irrespective of their contribution to the fit. For other variables, a p value of 0.05 was considered significant, and contribution to the model was based on the deviance estimate.

The first stool samples of cases and controls were used to study the presence of pathogens. Because of insufficient quantity of the first stool samples, the results for the bacterial tests for 88 cases and 29 controls were based on the second stool sample. Dientamoeba fragilis was considered a potentially pathogenic parasite, but was not included in the total of pathogens.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 REFERENCES
 
Participation and representativeness of the cohort
In total, 11,569 persons were invited, and 4,860 persons (42 percent) participated (figure 1). Participation was highest in the age groups up to 11 years (54 percent) and decreased with age (28 percent for ages 65 years and older). Participation was lower in the two most urbanized categories (28 and 40 percent) and in the western region of the country (33 percent). Of the 2,503 nonparticipants who supplied information on the reason for nonresponse, 154 persons (6 percent) responded that they never or hardly ever suffered from gastrointestinal symptoms. In accordance, persons who reported diarrhea in the 2 months prior to the beginning of the study were overrepresented (13.3 vs. 9.6 percent). In addition, persons born outside the Netherlands were underrepresented (2.4 vs. 7.5 percent) as were persons with a lower educational level (32.0 vs. 40.8 percent). In general, these differences between participants and nonparticipants were relatively small.



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FIGURE 1. Response of the cohort, the Netherlands, December 1998 to December 1999.

 
In comparison with the Dutch population, persons born outside the Netherlands were underrepresented (2 percent in the cohort and 10 percent in the Dutch population), as were persons with an intermediate educational level (35 vs. 54 percent). The western region of the country was underrepresented in the study (23 vs. 45 percent), as were areas with a very high and an intermediate degree of urbanization (10 vs. 19 percent and 13 vs. 21 percent).

Information was supplied for 121,682 person-weeks (2,340 person-years) of the possible maximum of 126,360 person-weeks (96 percent). Of these, 2,077 person-weeks (1.7 percent) were spent abroad. Of all participants, 99 percent supplied information for 23 weeks or more, and 76 percent supplied information for all 26 weeks. A total of 97 persons dropped out of the study. The most important reasons for loss to follow-up were switching to a nonparticipating general practitioner or a change in personal situation that made participation no longer feasible (e.g., hospitalization, new job).

Incidence
A total of 1,050 case episodes occurred during the follow-up period: 718 persons had one episode of gastroenteritis, 129 had two, 18 had three, and five had four.

The overall incidence standardized by age, gender, and cohort was 283 per 1,000 person-years (table 1). The incidence was slightly higher in the first cohort and was much higher in children aged 0–11 years compared with the older age groups. The peak was found in children aged 1–4 years. Furthermore, the incidence increased with educational level and was higher for persons who reported diarrhea in the 2 months prior to follow-up. The standardized incidence was the highest in January 1999 (figure 2). A second peak was observed in June 1999.


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TABLE 1. Incidence of gastroenteritis per 1,000 person-years by sociodemographic variables in a prospective population-based cohort study in the Netherlands, December 1998 to December 1999

 


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FIGURE 2. Incidence of gastroenteritis by 4-week period (crude and standardized by age, gender, and cohort), the Netherlands, December 1998 to December 1999.

 
Case-control study
Overall, 73 percent of eligible cases participated in the case-control component. Cases from the older age groups participated less than did those from the younger age groups, with the lowest participation in the adolescents (12–17 years). Of the invited controls, 90 percent participated (765 of 851).

A total of 713 cases and 684 controls submitted at least one stool sample. Of the first samples of cases, 68 percent were collected within 1 day after the onset of symptoms (maximum, 23 days after), and 98 percent were collected within 1 week after the onset.

Overall, in 46 percent of cases (standardized, 36 percent), a pathogen was detected (excluding D. fragilis, Blastocystis hominis, B. cereus, and other Bacillus species) (table 2). Viruses were the leading cause of gastroenteritis in cases, with NLV as the predominant one, followed by rotavirus and SLV. Viral agents were also detected in 0.6–5.2 percent of the controls. Bacteria were found in low percentages in cases, with Campylobacter as the most prominent one. Because young children were overrepresented, after standardization for age, the proportion of cases attributable to viruses was lower and that attributed to bacteria was higher. Bacterial agents were hardly present in controls. Analysis of only stool samples that were received within 4 days after the onset of symptoms had only a minor impact on the percentages positive for bacteria. Giardia lamblia was also a frequently detected pathogen in cases, but was detected in a similar percentage of controls. Bacterial toxins were detected in 8 percent of the cases, and in 5 percent, it was detected as the only cause of gastroenteritis, as well as in a substantial proportion of controls. Of the samples of cases that were tested for all pathogens, in 8 percent (23 of 291 samples), more than one pathogen was detected. In total, only 2 percent of cases reported use of antibiotics in the week before the onset of symptoms.


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TABLE 2. Microbiologic findings in cases and controls in the nested case-control component, the Netherlands, December 1998 to December 1999

 
For all age groups, NLV was the most frequent pathogen, with the exception of those aged 18–64 years, in which S. aureus was slightly more frequent and NLV was relatively low (table 3). In contrast, SLV was mostly observed in the three youngest age groups, with a decreasing frequency for those aged less than 1 year to those aged 5–11 years. A similar pattern was observed for adenovirus. Rotavirus was most frequent in the children younger than 1 year. Surprisingly, the proportion of rotavirus in adults and the elderly was similar to that in those aged 1–4 years. Astrovirus was detected mainly in the youngest age groups, but increased for those aged 0 to 5–11 years. In the age group 1–4 years and, to a lesser extent, the age group 5–11 years, G. lamblia was also common. Cryptosporidium was more restricted to the age group 1–4 years. S. aureus toxins were common in most age groups, with the exception of the adolescents and the elderly. C. perfringens toxin was detected mostly in the age groups 12 years and older, with the highest percentage in those aged 12–17 years. The age distributions of the different pathogens in controls was similar to those in cases (not shown).


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TABLE 3. Proportion of cases with specific pathogens in different age groups in cases of the case-control component, the Netherlands, December 1998 to December 1999

 
A pathogen was found in about half of the age groups up to age 11 years. The lowest percentage was found in those aged 12–17 years. The proportion of cases with D. fragilis increased up to age 5–11 years and decreased in the older age groups. The age distribution of pathogens that were detected in fewer than six cases was not presented in table 3 because the numbers per age group were too small to allow conclusions.

DISCUSSION
Response and incidence
This is one of the few population-based prospective studies on gastroenteritis in the world. A unique feature of our study was that we tested a broad panel of microorganisms by using recently developed techniques for some pathogens. In addition to a prospectively measured incidence rate, the results provide rarely available data on the relative importance of the various pathogens in all age groups throughout the community. This order of importance probably reflects the pattern in many industrialized countries and thus may be valuable for setting public health priorities for the control of gastroenteritis in these countries.

The standardized overall incidence of gastroenteritis in the Netherlands was 283 per 1,000 person-years, a lower estimate than that of 447 per 1,000 person-years found in a population-based study in the Netherlands in 1991 (13Go). Although it may reflect an actual decrease over this decade, it is more likely that the incidence in 1991 was overestimated, since response seemed strongly influenced by gastrointestinal symptoms. A comparable study in England over the period 1993–1995 reported an incidence of 190 per 1,000 person-years, which is significantly lower (14Go). Our case definition was stricter than that used in England (loose stools or significant vomiting), and therefore, the higher incidence cannot be explained by the difference in case definition. Furthermore, the percentage in which a pathogen was detected was similar in our study (46 percent) and in the English study (45 percent), and therefore, the difference in incidence cannot be explained by the inclusion of a larger proportion of noninfectious gastroenteritis (15Go). Since the methodologies of both studies were comparable, it is likely that the incidence in the Netherlands is indeed higher than that in England. For the United States, a much higher estimate of 790 per 1,000 person-years was recently reported (16Go). However, this rate is based mainly on retrospective self-reported symptoms, which are known to yield overestimates of the real incidence (14Go).

In our study, persons reporting diarrhea prior to the follow-up period were slightly overrepresented, and those with an intermediate educational level were underrepresented. However, the effect of these biases is very small: Correction for the educational level increased the incidence by 5 percent; correction for the overrepresentation of persons with diarrhea in the previous 2 months decreased the incidence with only 2 percent. The effect of the underrepresentation of persons born abroad, who tended to have a higher incidence, could not be estimated because no valid estimate of the incidence could be obtained for this small subgroup. To examine this specific group, a separate study would be needed with special focus on language problems and cultural barriers. The incidence might be underestimated because of underreporting of symptoms with increasing duration of follow-up; the incidence was higher at the beginning of the follow-up period for both cohorts. However, these peaks also coincided with the winter peak and the summer peak, known from other sources to occur in these weeks (17Go, 18Go). In general, we believe that our standardized estimate of the incidence of gastroenteritis is valid.

A higher incidence was found for persons with a higher educational level. In contrast, in developing countries, negative associations between educational level and incidence of diarrhea have been reported (19GoGo–21Go). This is mostly explained by a better knowledge of the concepts of hygiene and access to proper sanitation for the highly educated population. This explanation seems to be relevant for countries where the socioeconomic differences are large. However, in the Netherlands, socioeconomic differences are relatively small. The risk for the highly educated persons in our country might be associated with a higher income, resulting in more money to spend on, for instance, travel, eating in restaurants, and high-risk exotic foods. In addition, a study in the United States showed that risk behavior for foodborne infections, such as consumption of raw meat, was more common among persons with a higher education (22Go).

Microbiologic findings and response of cases and controls
In general, results are based on a 1-year period. For several pathogens, especially viruses, the seasonal peaks can differ in magnitude in different years. On the basis of laboratory surveillance data, the studied year did not seem to be an exceptional year.

Viral pathogens were the most important causes of gastroenteritis in community cases, with the largest percentage being attributable to NLV. This supports the finding of the English study, although their estimate was clearly lower than ours, probably because of the use of less sensitive electron microscopy for detection of these viruses (10Go, 15Go). The US estimate of 11 percent of cases attributable to NLV presented by Mead et al. (16Go) was based on the preliminary estimate of the winter season of our study (23Go). Bacterial pathogens were detected only in a small proportion of cases (2 percent) (after standardization, 5 percent). In England, the percentages attributable to Campylobacter and Salmonella were slightly higher than in our study, but were also secondary to viral agents (15Go). For the United States, the percentage attributable to bacterial agents was comparable with our estimate (16Go).

Among the parasites, G. lamblia was the most frequently detected (in approximately 5 percent of the cases). However, the percentage detected in controls was similar. The moment of sampling might be relevant here: The excretion of G. lamblia often starts 1 week after the beginning of symptoms, and first samples were collected as soon as possible after onset (24Go). This influence will be studied by future comparison of the percentage positive for G. lamblia in first and second samples. G. lamblia was more frequent in our study than in the English study. This might be due to the exclusion of cases with symptoms for more than 2 weeks in the English study and to the less sensitive testing method in their study (7Go). Remarkably, Cryptosporidium was also more common in our study than in the English study, in spite of the frequent occurrence of outbreaks of Cryptosporidium in England (25GoGo–27Go).

Due to the early time of sampling in this study, bacterial toxins were detected in 8 percent of the cases and contributed 5 percent to decreasing the diagnostic deficit. However, S. aureus toxins were also detected in a similar percentage of controls. In England as well as in the United States, both S. aureus and C. perfringens were present in less than 1 percent of all cases (15Go, 16Go).

The relative contributions of the different pathogens contrast sharply with results from general practitioner-based studies (6Go, 15Go). It is likely that this difference is related to the severity and duration of symptoms caused by the different groups of pathogens.

To our knowledge, our study is the first to present community-based age distributions of SLV cases and to present community-based data on NLV (and SLV) based on molecular detection methods. Since the development of RT-PCR for the detection of NLV, this pathogen was already shown to be the major cause of outbreaks in winter months in the Netherlands (10Go). This study showed that it is also the main pathogen in individual cases of all age groups.

While NLV was observed as the most frequent pathogen in all age groups, SLV was mainly restricted to the youngest age groups, with a clearly decreasing trend from those aged 0 years to those aged 5–11 years. This is consistent with studies that show that antibodies are acquired early in life and immunity protects the adults (28Go, 29Go). The proportion of cases in which astroviruses were detected increased slightly up to age 11 years, in contrast to several reviews that report infections mainly in very young children (28Go, 30Go, 31Go). Although a seroprevalence study in the Netherlands showed that antibodies against astrovirus can be detected in almost all persons aged 5 years and older, the proportion of cases with astrovirus was relatively low in all age groups, suggesting that the majority of seroconversions are due to asymptomatic infection (32Go). Alternatively, it is conceivable that high numbers of positives would have been detected by RT-PCR-based detection, as had been demonstrated in other studies (33Go, 34Go). The added value of RT-PCR in the detection of astroviruses will be evaluated in future experiments.

Annually, 4.5 million episodes of gastroenteritis occur in the Netherlands. For children under age 5 years, more than half have at least one episode each year. The incidence in the Netherlands is approximately 1.5 times as high as in England and approximately one quarter of the less precise estimate for the United States. Viral agents are the leading cause of illness, with NLV as the number one pathogen in almost all age groups. Clear differences in the relative importance of the various pathogens were observed between this community-based study and the general practice-based studies. In many countries, preventive measures are implemented to decrease bacterial infections. This study shows that prevention of viral infections, especially NLV, might significantly decrease the number of gastroenteritis cases in the community. However, to effectively determine intervention strategies, more information is needed on the relevant routes of transmission of NLV.


    ACKNOWLEDGMENTS
 
The authors thank the participating general practitioners and the Netherlands Institute for Primary Health Care (NIVEL) for their indispensable cooperation in the data collection. Furthermore, they thank Carolien de Jager and Anita Suijkerbuijk for their excellent coordination of the data collection and Denise Hoek, Joke Admiraal, Miranda Asbroek, Nahid Nozari, and Hanneke Deijl for their excellent assistance in performing the diagnostic tests. The authors also thank Frithjofna Abbink for her work on the design of the study, Dr. Nico Nagelkerke and Dr. Wilfrid van Pelt for their advice on the analyses, and the IID study team in London, England (LSHTM, PHLS/CDSC) for sharing their experiences.


    NOTES
 
Correspondence to Dr. Matty de Wit, Department of Infectious Diseases Epidemiology, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, the Netherlands (e-mail: matty.de.wit{at}rivm.nl).


    REFERENCES
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 MATERIALS AND METHODS
 RESULTS
 REFERENCES
 

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Received for publication October 9, 2000. Accepted for publication April 20, 2001.